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1. Genetically elevated high‐density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Author: Peloso, Gina M, van der Lee, Sven J, Project, International Genomics of Alzheimer's, Sims, R, van der Lee, SJ, Naj, AC, Bellenguez, C, Badarinarayan, N, Jakobsdottir, J, Kunkle, BW, Boland, A, Raybould, R, Bis, JC, Martin, ER, Grenier‐Boley, B, Heilmann‐Heimbach, S, Chouraki, V, Kuzma, AB, Sleegers, K, Vronskaya, M, Ruiz, A, Graham, RR, Olaso, R, Hoffmann, P, Grove, ML, Vardarajan, BN, Hiltunen, M, Nöthen, MM, White, CC, Hamilton‐Nelson, KL, Epelbaum, J, Maier, W, Choi, SH, Beecham, GW, Dulary, C, Herms, S, Smith, AV, Funk, CC, Derbois, Forstner, AJ, Ahmad, S, Li, H, Bacq, D, Harold, D, Satizabal, CL, Valladares, O, Squassina, A, Thomas, R, Brody, JA, Qu, L, Sánchez‐Juan, P, Morgan, T, Wolters, FJ, Zhao, Y, Garcia, FS, Denning, N, Fornage, M, Malamon, J, Naranjo, MCD, Majounie, E, Mosley, TH, Dombroski, B, Wallon, D, Lupton, MK, Dupuis, J, Whitehead, P, Fratiglioni, L, Medway, C, Jian, X, Mukherjee, S, Keller, L, Brown, K, Lin, H, Cantwell, LB, Panza, F, McGuinness, B, Moreno‐Grau, S, Burgess, JD, Solfrizzi, V, Proitsi, P, Adams, HH, Allen, M, Seripa, D, Pastor, P, Cupples, LA, Price, ND, Hannequin, D, Frank‐García, A, Levy, D, Chakrabarty, P, Caffarra, P, Giegling, I, Beiser, AS, Giedraitis, V, Hampel, H, Garcia, ME, Wang, X, Lannfelt, L, Mecocci, P, and Eiriksdottir, G
Subjects: Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease, Prevention, Genetics, Brain Disorders, Dementia, Atherosclerosis, Acquired Cognitive Impairment, Cardiovascular, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, 2.1 Biological and endogenous factors, Neurological, International Genomics of Alzheimer's Project, Cholesteryl ester transfer protein, HDL-C, Instrumental variables, Single nucleotide polymorphisms, Biological psychology
Abstract: IntroductionThere is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.MethodsTen single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.ResultsBased on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).DiscussionOur study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.
Published: 2018

2. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author: Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, deJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, and Chasman, DI
Subjects: Biological Psychology, Clinical and Health Psychology, Psychology, Human Genome, Neurosciences, Genetics, Clinical Research, Aging, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Cell Adhesion Molecules, Cognition, Cohort Studies, Executive Function, Female, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Introns, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Single Nucleotide, White People, gamma-Aminobutyric Acid, Generation Scotland, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
Published: 2016

3. A novel Alzheimer disease locus located near the gene encoding tau protein.

Author: Jun, G, Ibrahim-Verbaas, CA, Vronskaya, M, Lambert, J-C, Chung, J, Naj, AC, Kunkle, BW, Wang, L-S, Bis, JC, Bellenguez, C, Harold, D, Lunetta, KL, Destefano, AL, Grenier-Boley, B, Sims, R, Beecham, GW, Smith, AV, Chouraki, V, Hamilton-Nelson, KL, Ikram, MA, Fievet, N, Denning, N, Martin, ER, Schmidt, H, Kamatani, Y, Dunstan, ML, Valladares, O, Laza, AR, Zelenika, D, Ramirez, A, Foroud, TM, Choi, S-H, Boland, A, Becker, T, Kukull, WA, van der Lee, SJ, Pasquier, F, Cruchaga, C, Beekly, D, Fitzpatrick, AL, Hanon, O, Gill, M, Barber, R, Gudnason, V, Campion, D, Love, S, Bennett, DA, Amin, N, Berr, C, Tsolaki, Magda, Buxbaum, JD, Lopez, OL, Deramecourt, V, Fox, NC, Cantwell, LB, Tárraga, L, Dufouil, C, Hardy, J, Crane, PK, Eiriksdottir, G, Hannequin, D, Clarke, R, Evans, D, Mosley, TH, Letenneur, L, Brayne, C, Maier, W, De Jager, P, Emilsson, V, Dartigues, J-F, Hampel, H, Kamboh, MI, de Bruijn, RFAG, Tzourio, C, Pastor, P, Larson, EB, Rotter, JI, O'Donovan, MC, Montine, TJ, Nalls, MA, Mead, S, Reiman, EM, Jonsson, PV, Holmes, C, St George-Hyslop, PH, Boada, M, Passmore, P, Wendland, JR, Schmidt, R, Morgan, K, Winslow, AR, Powell, JF, Carasquillo, M, Younkin, SG, Jakobsdóttir, J, Kauwe, JSK, Wilhelmsen, KC, Rujescu, D, Nöthen, MM, and Hofman, A
Subjects: IGAP Consortium, Chromosomes, Human, Pair 17, Humans, Alzheimer Disease, tau Proteins, Polymorphism, Single Nucleotide, Apolipoprotein E4, Genome-Wide Association Study, Alzheimer's Disease, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Human Genome, Neurodegenerative, Neurosciences, Acquired Cognitive Impairment, Genetics, Brain Disorders, Aging, 2.1 Biological and endogenous factors, Neurological, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P
Published: 2016

4. Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Author: Luo, X-J, Li, M, Huang, L, Steinberg, S, Mattheisen, M, Liang, G, Donohoe, G, Shi, Y, Chen, C, Yue, W, Alkelai, A, Lerer, B, Li, Z, Yi, Q, Rietschel, M, Cichon, S, Collier, DA, Tosato, S, Suvisaari, J, Rujescu, Dan, Golimbet, V, Silagadze, T, Durmishi, N, Milovancevic, MP, Stefansson, H, Schulze, TG, Nöthen, MM, Lyne, R, Morris, DW, Gill, M, Corvin, A, Zhang, D, Dong, Q, Moyzis, RK, Stefansson, K, Sigurdsson, E, Hu, F, Su, B, and Gan, L
Subjects: Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Mental Health, Serious Mental Illness, Genetics, Brain Disorders, Human Genome, Schizophrenia, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Mental health, Alleles, Asian People, Brain, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Case-Control Studies, Cognition, Databases, Genetic, Down-Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Personality, Polymorphism, Single Nucleotide, Protein Interaction Maps, Schizophrenic Psychology, White People, association, CAMKK2, eQTL, expression, protein-protein interaction, schizophrenia, MooDS SCZ Consortium, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract: Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
Published: 2014

5. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

Author: Børglum, AD, Demontis, D, Grove, J, Pallesen, J, Hollegaard, MV, Pedersen, CB, Hedemand, A, Mattheisen, M, Uitterlinden, A, Nyegaard, M, Ørntoft, T, Wiuf, C, Didriksen, M, Nordentoft, M, Nöthen, MM, Rietschel, M, Ophoff, RA, Cichon, S, Yolken, RH, Hougaard, DM, Mortensen, PB, and Mors, O
Subjects: Genetics, Schizophrenia, Brain Disorders, Mental Health, Human Genome, Infectious Diseases, Serious Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, ARNTL Transcription Factors, Cadherins, Case-Control Studies, Cytomegalovirus Infections, Denmark, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Germany, Homeodomain Proteins, Humans, Maternal Exposure, Polymorphism, Single Nucleotide, Sorting Nexins, Transcription Factors, White People, Zinc Finger E-box-Binding Homeobox 1, alpha Catenin, CTNNA3, gene-environment interaction, GWAS, GWIS, region-wise analysis, ZEB1, GROUP investigators10, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.
Published: 2014

6. Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets.

Author: Degenhardt, F, Priebe, L, Meier, S, Lennertz, L, Streit, F, Witt, SH, Hofmann, A, Becker, T, Mössner, R, Maier, W, Nenadic, I, Sauer, H, Mattheisen, M, Buizer-Voskamp, J, Ophoff, RA, GROUP Consortium, Rujescu, D, Giegling, I, Ingason, A, Wagner, M, Delobel, B, Andrieux, J, Meyer-Lindenberg, A, Heinz, A, Walter, H, Moebus, S, Corvin, A, Wellcome Trust Case Control Consortium 2, International Schizophrenia Consortium, Rietschel, M, Nöthen, MM, and Cichon, S
Subjects: GROUP Consortium, Wellcome Trust Case Control Consortium 2, International Schizophrenia Consortium, Humans, Genetic Predisposition to Disease, Schizophrenia, Gene Duplication, Adult, Aged, Middle Aged, Europe, Female, Male, Protein-Tyrosine Kinases, DGCR2, exome-sequencing, intellectual disability, RB1-inducible coiled-coil 1, schizoaffective disorder, Clinical Sciences, Public Health and Health Services, Psychology
Abstract: Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.
Published: 2013

7. Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Author: Law, PJ, Timofeeva, M, Fernandez-Rozadilla, C, Broderick, P, Studd, J, Fernandez-Tajes, J, Farrington, S, Svinti, V, Palles, C, Orlando, G, Sud, A, Holroyd, A, Penegar, S, Theodoratou, E, Vaughan-Shaw, P, Campbell, H, Zgaga, L, Hayward, C, Campbell, A, Harris, S, Deary, IJ, Starr, J, Gatcombe, L, Pinna, M, Briggs, S, Martin, L, Jaeger, E, Sharma-Oates, A, East, J, Leedham, S, Arnold, R, Johnstone, E, Wang, H, Kerr, D, Kerr, R, Maughan, T, Kaplan, R, Al-Tassan, N, Palin, K, Hänninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepistö, A, Böhm, J, Mecklin, J-P, Buchanan, DD, Win, A-K, Hopper, J, Jenkins, ME, Lindor, NM, Newcomb, PA, Gallinger, S, Duggan, D, Casey, G, Hoffmann, P, Nöthen, MM, Jöckel, K-H, Easton, DF, Pharoah, PDP, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Consortium, Practical, Harkin, A, Allan, K, McQueen, J, Paul, J, Iveson, T, Saunders, M, Butterbach, K, Chang-Claude, J, Hoffmeister, M, Brenner, H, Kirac, I, Matošević, P, Hofer, P, Brezina, S, Gsur, A, Cheadle, JP, Aaltonen, LA, Tomlinson, I, Houlston, RS, Dunlop, MG, Law, Philip J [0000-0001-9663-4611], Timofeeva, Maria [0000-0002-2503-4253], Fernandez-Rozadilla, Ceres [0000-0001-7330-4804], Broderick, Peter [0000-0002-8348-5829], Studd, James [0000-0002-7157-754X], Farrington, Susan [0000-0001-5955-7389], Svinti, Victoria [0000-0001-9926-0416], Sud, Amit [0000-0002-6133-0164], Hayward, Caroline [0000-0002-9405-9550], Campbell, Archie [0000-0003-0198-5078], Martin, Lynn [0000-0003-3962-389X], East, James [0000-0001-8035-3700], Kaplan, Richard [0000-0002-0189-8348], Al-Tassan, Nada [0000-0001-9076-0334], Palin, Kimmo [0000-0002-4621-6128], Salomaa, Veikko [0000-0001-7563-5324], Buchanan, Daniel D [0000-0003-2225-6675], Win, Aung-Ko [0000-0002-2794-5261], Jenkins, Mark E [0000-0002-8964-6160], Easton, Douglas F [0000-0003-2444-3247], Pharoah, Paul DP [0000-0001-8494-732X], Eeles, Rosalind A [0000-0002-3698-6241], Muir, Kenneth [0000-0001-6429-988X], Pashayan, Nora [0000-0003-0843-2468], Harkin, Andrea [0000-0002-8831-7381], Paul, James [0000-0001-7367-5816], Hofer, Philipp [0000-0003-2550-6019], Brezina, Stefanie [0000-0001-5238-6900], Cheadle, Jeremy P [0000-0001-9453-8458], Tomlinson, Ian [0000-0003-3037-1470], Houlston, Richard S [0000-0002-5268-0242], and Apollo - University of Cambridge Repository
Subjects: Male, Science, Inheritance Patterns, cancer genetics, Datasets as Topic, colorectal cancer, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, White People, Asian People, Risk Factors, Cancer genomics, Humans, Genetic Predisposition to Disease, lcsh:Science, Cancer genetics, neoplasms, cancer genomics, genomiikka, Middle Aged, Colorectal cancer, digestive system diseases, peräsuolisyöpä, syöpägeenit, Genetic Loci, Case-Control Studies, genome-wide association studies, lcsh:Q, syöpätaudit, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention., In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
Published: 2019

8. HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Author: Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, Squassina, A, Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, and Squassina, A
Abstract: Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Published: 2021

9. Prediction of lithium response using genomic data

Author: Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, Alda, M, Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, and Alda, M
Abstract: Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
Published: 2021

10. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies

Author: Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, Agrawal, A, Munn-Chernoff, MA, Johnson, EC, Chou, YL, Coleman, JRI, Thornton, LM, Walters, RK, Yilmaz, Z, Baker, JH, Hübel, C, Gordon, S, Medland, SE, Watson, HJ, Gaspar, HA, Bryois, J, Hinney, A, Leppä, VM, Mattheisen, M, Ripke, S, Yao, S, Giusti-Rodríguez, P, Hanscombe, KB, Adan, RAH, Alfredsson, L, Ando, T, Andreassen, OA, Berrettini, WH, Boehm, I, Boni, C, Boraska Perica, V, Buehren, K, Burghardt, R, Cassina, M, Cichon, S, Clementi, M, Cone, RD, Courtet, P, Crow, S, Crowley, JJ, Danner, UN, Davis, OS, Zwaan, M, Dedoussis, G, Degortes, D, DeSocio, JE, Dick, DM, Dikeos, D, Dina, C, Dmitrzak-Weglarz, M, Docampo, E, Duncan, LE, Egberts, K, Ehrlich, S, Escaramís, G, Esko, T, Estivill, X, Farmer, A, Favaro, A, Fernández-Aranda, F, Fichter, MM, Fischer, K, Föcker, M, Foretova, L, Forstner, AJ, Forzan, M, Franklin, CS, Gallinger, S, Giegling, I, Giuranna, J, Gonidakis, F, Gorwood, P, Gratacos Mayora, M, Guillaume, S, Guo, Y, Hakonarson, H, Hatzikotoulas, K, Hauser, J, Hebebrand, J, Helder, SG, Herms, S, Herpertz-Dahlmann, B, Herzog, W, Huckins, LM, Hudson, JI, Imgart, H, Inoko, H, Janout, V, Jiménez-Murcia, S, Julià, A, Kalsi, G, Kaminská, D, Karhunen, L, Karwautz, A, Kas, MJH, Kennedy, JL, Keski-Rahkonen, A, Kiezebrink, K, Kim, YR, Klump, KL, Knudsen, GP, La Via, MC, Le Hellard, S, Levitan, RD, Li, D, Lilenfeld, L, Lin, BD, Lissowska, J, Luykx, J, Magistretti, PJ, Maj, M, Mannik, K, Marsal, S, Marshall, CR, Mattingsdal, M, McDevitt, S, McGuffin, P, Metspalu, A, Meulenbelt, I, Micali, N, Mitchell, K, Monteleone, A M, Monteleone, P, Nacmias, B, Navratilova, M, Ntalla, I, O'Toole, JK, Ophoff, Roel, Padyukov, L, Palotie, A, Pantel, J, Papezova, H, Pinto, D, Rabionet, R, Raevuori, A, Ramoz, N, Reichborn-Kjennerud, T, Ricca, V, Ripatti, S, Ritschel, F, Roberts, M, Rotondo, A, Rujescu, D, Rybakowski, F, Santonastaso, P, Scherag, A, Scherer, SW, Schmidt, U, Schork, NJ, Schosser, A, Seitz, J, Slachtova, L, Slagboom, PE, Slof-Op't Landt, MCT, Slopien, A, Sorbi, S, ?wi?tkowska, B, Szatkiewicz, JP, Tachmazidou, I, Tenconi, E, Tortorella, A, Tozzi, F, Treasure, J, Tsitsika, A, Tyszkiewicz-Nwafor, M, Tziouvas, K, van Elburg, AA, van Furth, EF, Wagner, G, Walton, E, Widen, E, Zeggini, E, Zerwas, S, Zipfel, S, Bergen, AW, Boden, JM, Brandt, H, Crawford, S, Halmi, KA, Horwood, LJ, Johnson, C, Kaplan, AS, Kaye, WH, Mitchell, J E, Olsen, CM, Pearson, JF, Pedersen, NL, Strober, M, Werge, T, Whiteman, DC, Woodside, DB, Grove, J, Henders, AK, Larsen, J T, Parker, R, Petersen, LV, Jordan, J, Kennedy, MA, Birgegård, A, Lichtenstein, P, Norring, C, Landén, M, Mortensen, PB, Polimanti, R, McClintick, JN, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, L S, Clarke, TK, Degenhardt, F, Docherty, AR, Edwards, AC, Foo, JC, Fox, L, Frank, J, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Hodgkinson, C, Hoffmann, P, Hottenga, JJ, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Peterson, RE, Ryu, E, Saccone, N L, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JCY, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Zhou, H, Boardman, JD, Chen, D, Choi, D S, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Frye, MA, Gäebel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Koller, G, Kramer, J (John), Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Männistö, S, Müller-Myhsok, B, Murray, AD, Nurnberger, JI, Preuss, U, Räikkönen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, SH, Wodarz, N, Zill, P, Adkins, DE, Boomsma, DI, Bierut, LJ, Brown, S, Bucholz, KK, Costello, EJ, Wit, HJ, Diazgranados, N, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Iacono, WG, Johnson, E O, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lind, PA, McGue, M, MacKillop, J, Madden, PA, Maes, HH, Magnusson, PKE, Nelson, EC, Nöthen, MM, Palmer, AA, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, RJ, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Wade, TD, Heath, AC, Montgomery, GW, Martin, NG, Sullivan, PF, Kaprio, J, Breen, G, Gelernter, J, Edenberg, HJ, Bulik, CM, and Agrawal, A
Abstract: Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotyp
Published: 2021

11. A novel Alzheimer disease locus located near the gene encoding tau protein

Author: Jun, G, Ibrahim-Verbaas, CA, Vronskaya, M, Lambert, J-C, Chung, J, Naj, AC, Kunkle, BW, Wang, L-S, Bis, JC, Bellenguez, C, Harold, D, Lunetta, KL, Destefano, AL, Grenier-Boley, B, Sims, R, Beecham, GW, Smith, AV, Chouraki, V, Hamilton-Nelson, KL, Ikram, MA, Fievet, N, Denning, N, Martin, ER, Schmidt, H, Kamatani, Y, Dunstan, ML, Valladares, O, Laza, AR, Zelenika, D, Ramirez, A, Foroud, TM, Choi, S-H, Boland, A, Becker, T, Kukull, WA, Van Der Lee, SJ, Pasquier, F, Cruchaga, C, Beekly, D, Fitzpatrick, AL, Hanon, O, Gill, M, Barber, R, Gudnason, V, Campion, D, Love, S, Bennett, DA, Amin, N, Berr, C, Tsolaki, Magda, Buxbaum, JD, Lopez, OL, Deramecourt, V, Fox, NC, Cantwell, LB, Tárraga, L, Dufouil, C, Hardy, J, Crane, PK, Eiriksdottir, G, Hannequin, D, Clarke, R, Evans, D, Mosley, TH, Letenneur, L, Brayne, C, Maier, W, De Jager, P, Emilsson, V, Dartigues, J-F, Hampel, H, Kamboh, MI, De Bruijn, RFAG, Tzourio, C, Pastor, P, Larson, EB, Rotter, JI, O'Donovan, MC, Montine, TJ, Nalls, MA, Mead, S, Reiman, EM, Jonsson, PV, Holmes, C, St George-Hyslop, PH, Boada, M, Passmore, P, Wendland, Schmidt, R, Morgan, K, Winslow, AR, Powell, JF, Carasquillo, M, Younkin, SG, Jakobsdóttir, J, Kauwe, JSK, Wilhelmsen, KC, Rujescu, D, Nöthen, MM, Hofman, A, Jones, L, IGAP Consortium, Haines, JL, Psaty, BM, Van Broeckhoven, C, Holmans, P, Launer, LJ, Mayeux, R, Lathrop, M, Goate, AM, Escott-Price, V, Seshadri, S, Pericak-Vance, MA, Amouyel, P, Williams, J, Van Duijn, CM, Schellenberg, GD, Farrer, LA, Chouraki, V [0000-0002-4698-1794], Amouyel, P [0000-0001-9088-234X], and Apollo - University of Cambridge Repository
Subjects: Alzheimer Disease, Apolipoprotein E4, Humans, tau Proteins, Polymorphism, Single Nucleotide, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P
Published: 2019
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12. Polygenic risk and hazard scores for Alzheimer's disease prediction

Author: Leonenko, G, Sims, R, Shoai, M, Frizzati, A, Bossù, P, Spalletta, G, Fox, Nc, Williams, J, for the GERAD consortium: Hardy, J, Escott-Price, V, Tsolaki, M, Craig, D, Avramidou, D, Germanou, A, Koutroumani, M, Gkatzima, O, Hampel, H, Kehoe, Pg, Love, S, Rubinsztein, Dc, Frölich, L, Mcguinness, B, Johnston, Ja, Passmore, P, Drichel, D, Rossor, M, Schott, Jm, Warren, Jd, Bras, J, Guerreiro, R, Kawalia, A, Hughes, Jt, Patel, Y, Lupton, Mk, Proitsi, P, Powell, J, Kauwe, Jsk, Mancuso, M, Bonuccelli, U, Uphill, J, Fisher, E, Masullo, C, Soininen, H, Bisceglio, G, Ma, L, Dickson, Dw, Graff‐radford, Nr, Carrasquillo, Mm, Younkin, Sg, Sandro Sorbi, S, Daniilidou, M, Hodges, A, Galimberti, D, Scarpini, E, Scherer, M, Peters, O, Ramirez, A, Leber, M, Pichler, S, Mayhaus, M, Gu, W, Riemenschneider, M, Wiltfang, J, Heun, R, Kölsch, H, Kornhuber, J, Heuser, I, Rujescu, D, Hartmann, Am, Giegling, I, Hüll, M, Lovestone, S, Cruchaga, C, Morris, J, Mayo, K, Feulner, T, Sussams, R, Holmes, C, Mann, D, Pickering‐brown, S, Hooper, Nm, Mcquillin, A, Livingston, G, Bass, Nj, Vronskaya, M, Morgan, T, Denning, N, Cushion, Td, Jones, L, Marshall, R, Meggy, A, Menzies, G, Grozeva, D, O'Donovan, Mc, Owen, Mj, Holmans, Pa, Salani, F, Russo, G, Maier, W, Jessen, F, Wichmann, H-E, Morgan, K, Goate, Am, Vellas, B, Vardy, E, Moebus, S, Jöckel, K-H, Dichgans, M, Klopp, N, Turton, J, Lord, J, Brown, K, Medway, C, Nöthen, Mm, Hoffmann, P, Daniele, A, Bayer, A, Gallacher, J, van den Bussche, H, Brayne, C, Riedel‐heller, S, Powell, Jf, Al‐chalabi, A, Shaw, Ce, Kloszewska, I, Pastor, P, Diez‐fairen, M, Lynch, A, Lawlor, B, Gill, M, Coto, E, Alvarez, V, Singleton, Ab, Collinge, J, Mead, S, Ryan, N, Nacmias, B, Ortega‐cubero, S, Rodriguez‐rodriguez, E, Sanchez‐juan, P, Shofany, J, Banaj, N, Ciullo, V, Sacchinelli, E, Robert, Clarke, A David Smith, Donald, Warden, Yoav, Ben‐shlomo, Chiara, Cupidi, Raffaele Giovanni Maletta, Runi, Gallo, M, Harold, D, Cecchetti, R, Mecocci, P, Boccardi, V, Warner, N, Wilcock, G, Deloukas, P, Gwilliam, R, Corcoran, C, Tschanz, J, Munger, R., and Consortium, Gerad
Subjects: Male, Multifactorial Inheritance, Polygenic risk, Alzheimer's disease, hazard score, Polymorphism, Single Nucleotide, Settore MED/26 - NEUROLOGIA, Apolipoproteins E, Alzheimer Disease, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Research Articles, Research Article, Genome-Wide Association Study, Proportional Hazards Models
Abstract: Objective: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).
Published: 2019

13. Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Author: Went, M, Sud, A, Försti, A, Halvarsson, BM, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Jöckel, KH, Johnsson, E, Kristinsson, SY, Mellqvist, UH, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, ZS, Muir, K, Pashayan, N, Nickel, J, Nöthen, MM, Rafnar, T, Ross, FM, da Silva Filho, MI, Thomsen, H, Turesson, I, Vangsted, A, Andersen, NF, Waage, A, Walker, BA, Wihlborg, AK, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Goldschmidt, H, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Hemminki, K, Nilsson, B, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, The PRACTICAL Consortium, and Claessens, Frank
Subjects: Male, Quality Control, Risk, Chromatin Immunoprecipitation, Genotype, European Continental Ancestry Group, Quantitative Trait Loci, Bayes Theorem, Polymorphism, Single Nucleotide, Chromatin, Gene Expression Regulation, Humans, Female, Genetic Predisposition to Disease, Multiple Myeloma, Promoter Regions, Genetic, Genome-Wide Association Study
Abstract: © 2018, The Author(s). Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published
Published: 2018

14. Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia

Author: Vijayakrishnan, J, Studd, J, Broderick, P, Kinnersley, B, Holroyd, A, Law, PJ, Kumar, R, Allan, JM, Harrison, CJ, Moorman, AV, Vora, A, Roman, E, Rachakonda, S, Kinsey, SE, Sheridan, E, Thompson, PD, Irving, JA, Koehler, R, Hoffmann, P, Nöthen, MM, Heilmann-Heimbach, S, Jöckel, KH, Easton, DF, Pharaoh, PDP, Dunning, AM, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, Z, Muir, K, Pashayan, N, Greaves, M, Zimmerman, M, Bartram, CR, Schrappe, M, Stanulla, M, Hemminki, K, Houlston, RS, Henderson, BE, Haiman, CA, Benlloch, S, Schumacher, FR, Olama, AAA, Berndt, SI, Conti, DV, Wiklund, F, Chanock, S, Stevens, VL, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Schleutker, J, Albanes, D, Weinstein, S, Wolk, A, West, C, Mucci, L, Cancel-Tassin, G, Koutros, S, Sorensen, KD, Maehle, L, Neal, DE, Travis, RC, Hamilton, RJ, Ingles, SA, Rosenstein, B, Lu, YJ, Giles, GG, Kibel, AS, Vega, A, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, The PRACTICAL Consortium, and Claessens, Frank
Subjects: Male, Oncogene Proteins, Fusion, Glycosyltransferases, Prognosis, Polymorphism, Single Nucleotide, HLA Antigens, Risk Factors, Child, Preschool, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Core Binding Factor Alpha 2 Subunit, Humans, Female, Genetic Predisposition to Disease, Child, Genome-Wide Association Study
Abstract: © 2018 The Author(s). Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology. ispartof: Nature Communications vol:9 issue:1 ispartof: location:England status: published
Published: 2018

15. Quality control and conduct of genome-wide association meta-analyses

Author: Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis GR, Absher D, Alavere H, Albrecht E, Allen HL, Almgren P, Amin N, Amouyel P, Anderson D, Arnold AM, Arveiler D, Aspelund T, Asselbergs FW, Assimes TL, Atalay M, Attwood AP, Atwood LD, Bakker SJ, Balkau B, Balmforth AJ, Barlassina C, Barroso I, Basart H, Bauer S, Beckmann JS, Beilby JP, Bennett AJ, Ben Shlomo Y, Bergman RN, Bergmann S, Berndt SI, Biffar R, Di Blasio AM, Boehm BO, Boehnke M, Boeing H, Boerwinkle E, Bolton JL, Bonnefond A, Bonnycastle LL, Boomsma DI, Borecki IB, Bornstein SR, Bouatia Naji N, Boucher G, Bragg Gresham JL, BRAMBILLA, PAOLO, Bruinenberg M, Buchanan TA, Buechler C, Cadby G, Campbell H, Caulfield MJ, Cavalcanti Proença C, CESANA, GIANCARLO, Chanock SJ, Chasman DI, Chen YD, Chines PS, Clegg DJ, Coin L, Collins FS, Connell JM, Cookson W, Cooper MN, Croteau Chonka DC, Cupples LA, Cusi D, Day FR, Day IN, Dedoussis GV, Dei M, Deloukas P, Dermitzakis ET, Dimas AS, Dimitriou M, Dixon AL, Dörr M, van Duijn CM, Ebrahim S, Edkins S, Eiriksdottir G, Eisinger K, Eklund N, Elliott P, Erbel R, Erdmann J, Erdos MR, Eriksson JG, Esko T, Estrada K, Evans DM, de Faire U, Fall T, Farrall M, Feitosa MF, Ferrario MM, Ferreira T, Ferrières J, Fischer K, Fisher E, Fowkes G, Fox CS, Franke L, Franks PW, Fraser RM, Frau F, Frayling T, Freimer NB, Froguel P, Fu M, Gaget S, Ganna A, Gejman PV, Gentilini D, Geus EJ, Gieger C, Gigante B, Gjesing AP, Glazer NL, Goddard ME, Goel A, Grallert H, Gräßler J, Grönberg H, Groop LC, Groves CJ, Gudnason V, Guiducci C, Gustafsson S, Gyllensten U, Hall AS, Hall P, Hallmans G, Hamsten A, Hansen T, Haritunians T, Harris TB, van der Harst P, Hartikainen AL, Hassanali N, Hattersley AT, Havulinna AS, Hayward C, Heard Costa NL, Heath AC, Hebebrand J, Heid IM, den Heijer M, Hengstenberg C, Herzig KH, Hicks AA, Hingorani A, Hinney A, Hirschhorn JN, Hofman A, Holmes CC, Homuth G, Hottenga JJ, Hovingh KG, Hu FB, Hu YJ, Huffman JE, Hui J, Huikuri H, Humphries SE, Hung J, Hunt SE, Hunter D, Hveem K, Hyppönen E, Igl W, Illig T, Ingelsson E, Iribarren C, Isomaa B, Jackson AU, Jacobs KB, James AL, Jansson JO, Jarick I, Jarvelin MR, Jöckel KH, Johansson Å, Johnson T, Jolley J, Jørgensen T, Jousilahti P, Jula A, Justice AE, Kaakinen M, Kähönen M, Kajantie E, Kanoni S, Kao WH, Kaplan LM, Kaplan RC, Kaprio J, Kapur K, Karpe F, Kathiresan S, Kee F, Keinanen Kiukaanniemi SM, Ketkar S, Kettunen J, Khaw KT, Kiemeney LA, Kilpeläinen TO, Kinnunen L, Kivimaki M, Kivmaki M, Van der Klauw MM, Kleber ME, Knowles JW, Koenig W, Kolcic I, Kolovou G, König IR, Koskinen S, Kovacs P, Kraft P, Kraja AT, Kristiansson K, KrjutÅjkov K, Kroemer HK, Krohn JP, Krzelj V, Kuh D, Kulzer JR, Kumari M, Kutalik Z, Kuulasmaa K, Kuusisto J, Kvaloy K, Laakso M, Laitinen JH, Lakka TA, Lamina C, Langenberg C, Lantieri O, Lathrop GM, Launer LJ, Lawlor DA, Lawrence RW, Leach IM, Lecoeur C, Lee SH, Lehtimäki T, Leitzmann MF, Lettre G, Levinson DF, Li G, Li S, Liang L, Lin DY, Lind L, Lindgren CM, Lindström J, Liu J, Liuzzi A, Locke AE, Lokki ML, Loley C, Loos RJ, Lorentzon M, Luan J, Luben RN, Ludwig B, Madden PA, Mägi R, Magnusson PK, Mangino M, Manunta P, Marek D, Marre M, Martin NG, März W, Maschio A, Mathieson I, McArdle WL, McCaroll SA, McCarthy A, McCarthy MI, McKnight B, Medina Gomez C, Medland SE, Meitinger T, Metspalu A, van Meurs JB, Meyre D, Midthjell K, Mihailov E, Milani L, Min JL, Moebus S, Moffatt MF, Mohlke KL, Molony C, Monda KL, Montgomery GW, Mooser V, Morken MA, Morris AD, Morris AP, Mühleisen TW, Müller Nurasyid M, Munroe PB, Musk AW, Narisu N, Navis G, Neale BM, Nelis M, Nemesh J, Neville MJ, Ngwa JS, Nicholson G, Nieminen MS, Njølstad I, Nohr EA, Nolte IM, North KE, Nöthen MM, Nyholt DR, O'Connell JR, Ohlsson C, Oldehinkel AJ, van Ommen GJ, Ong KK, Oostra BA, Ouwehand WH, Palmer CN, Palmer LJ, Palotie A, Paré G, Parker AN, Paternoster L, Pawitan Y, Pechlivanis S, Peden JF, Pedersen NL, Pedersen O, Pellikka N, Peltonen L, Penninx B, Perola M, Perry JR, Person T, Peters A, Peters MJ, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Power C, Pramstaller PP, Preuss M, Price JF, Prokopenko I, Province MA, Psaty BM, Purcell S, Pütter C, Qi L, Quertermous T, Radhakrishnan A, Raitakari O, Randall JC, Rauramaa R, Rayner NW, Rehnberg E, Rendon A, Ridderstråle M, Ridker PM, Ripatti S, Rissanen A, Rivadeneira F, Rivolta C, Robertson NR, Rose LM, Rudan I, Saaristo TE, Sager H, Salomaa V, Samani NJ, Sambrook JG, Sanders AR, Sandholt C, Sanna S, Saramies J, Schadt EE, Scherag A, Schipf S, Schlessinger D, Schreiber S, Schunkert H, Schwarz PE, Scott LJ, Shi J, Shin SY, Shuldiner AR, Shungin D, Signorini S, Silander K, Sinisalo J, Skrobek B, Smit JH, Smith AV, Smith GD, Snieder H, Soranzo N, Sørensen TI, Sovio U, Spector TD, Speliotes EK, Stančáková A, Stark K, Stefansson K, Steinthorsdottir V, Stephens JC, Stirrups K, Stolk RP, Strachan DP, Strawbridge RJ, Stringham HM, Stumvoll M, Surakka I, Swift AJ, Syvanen AC, Tammesoo ML, Teder Laving M, Teslovich TM, Teumer A, Theodoraki EV, Thomson B, Thorand B, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tönjes A, Tregouet DA, Tremoli E, Trip MD, Tuomi T, Tuomilehto J, Tyrer J, Uda M, Uitterlinden AG, Usala G, Uusitupa M, Valle TT, Vandenput L, Vatin V, Vedantam S, de Vegt F, Vermeulen SH, Viikari J, Virtamo J, Visscher PM, Vitart V, Van Vliet Ostaptchouk JV, Voight BF, Vollenweider P, Volpato CB, Völzke H, Waeber G, Waite LL, Wallaschofski H, Walters GB, Wang Z, Wareham NJ, Watanabe RM, Watkins H, Weedon MN, Welch R, Weyant RJ, Wheeler E, White CC, Wichmann HE, Widen E, Wild SH, Willemsen G, Willer CJ, Wilsgaard T, Wilson JF, van Wingerden S, Winkelmann BR, Winkler TW, Witte DR, Witteman JC, Wolffenbuttel BH, Wong A, Wood AR, Workalemahu T, Wright AF, Yang J, Yarnell JW, Zgaga L, Zhao JH, Zillikens MC, Zitting P, Zondervan KT, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Winkler, T, Day, F, Croteau Chonka, D, Wood, A, Locke, A, Mägi, R, Ferreira, T, Fall, T, Graff, M, Justice, A, Luan, J, Gustafsson, S, Randall, J, Vedantam, S, Workalemahu, T, Kilpeläinen, T, Scherag, A, Esko, T, Kutalik, Z, Heid, I, Loos, R, Abecasis, G, Absher, D, Alavere, H, Albrecht, E, Allen, H, Almgren, P, Amin, N, Amouyel, P, Anderson, D, Arnold, A, Arveiler, D, Aspelund, T, Asselbergs, F, Assimes, T, Atalay, M, Attwood, A, Atwood, L, Bakker, S, Balkau, B, Balmforth, A, Barlassina, C, Barroso, I, Basart, H, Bauer, S, Beckmann, J, Beilby, J, Bennett, A, Ben Shlomo, Y, Bergman, R, Bergmann, S, Berndt, S, Biffar, R, Di Blasio, A, Boehm, B, Boehnke, M, Boeing, H, Boerwinkle, E, Bolton, J, Bonnefond, A, Bonnycastle, L, Boomsma, D, Borecki, I, Bornstein, S, Bouatia Naji, N, Boucher, G, Bragg Gresham, J, Brambilla, P, Bruinenberg, M, Buchanan, T, Buechler, C, Cadby, G, Campbell, H, Caulfield, M, Cavalcanti Proença, C, Cesana, G, Chanock, S, Chasman, D, Chen, Y, Chines, P, Clegg, D, Coin, L, Collins, F, Connell, J, Cookson, W, Cooper, M, Cupples, L, Cusi, D, Day, I, Dedoussis, G, Dei, M, Deloukas, P, Dermitzakis, E, Dimas, A, Dimitriou, M, Dixon, A, Dörr, M, van Duijn, C, Ebrahim, S, Edkins, S, Eiriksdottir, G, Eisinger, K, Eklund, N, Elliott, P, Erbel, R, Erdmann, J, Erdos, M, Eriksson, J, Estrada, K, Evans, D, de Faire, U, Farrall, M, Feitosa, M, Ferrario, M, Ferrières, J, Fischer, K, Fisher, E, Fowkes, G, Fox, C, Franke, L, Franks, P, Fraser, R, Frau, F, Frayling, T, Freimer, N, Froguel, P, Fu, M, Gaget, S, Ganna, A, Gejman, P, Gentilini, D, Geus, E, Gieger, C, Gigante, B, Gjesing, A, Glazer, N, Goddard, M, Goel, A, Grallert, H, Gräßler, J, Grönberg, H, Groop, L, Groves, C, Gudnason, V, Guiducci, C, Gyllensten, U, Hall, A, Hall, P, Hallmans, G, Hamsten, A, Hansen, T, Haritunians, T, Harris, T, van der Harst, P, Hartikainen, A, Hassanali, N, Hattersley, A, Havulinna, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, den Heijer, M, Hengstenberg, C, Herzig, K, Hicks, A, Hingorani, A, Hinney, A, Hirschhorn, J, Hofman, A, Holmes, C, Homuth, G, Hottenga, J, Hovingh, K, Hu, F, Hu, Y, Huffman, J, Hui, J, Huikuri, H, Humphries, S, Hung, J, Hunt, S, Hunter, D, Hveem, K, Hyppönen, E, Igl, W, Illig, T, Ingelsson, E, Iribarren, C, Isomaa, B, Jackson, A, Jacobs, K, James, A, Jansson, J, Jarick, I, Jarvelin, M, Jöckel, K, Johansson, Å, Johnson, T, Jolley, J, Jørgensen, T, Jousilahti, P, Jula, A, Kaakinen, M, Kähönen, M, Kajantie, E, Kanoni, S, Kao, W, Kaplan, L, Kaplan, R, Kaprio, J, Kapur, K, Karpe, F, Kathiresan, S, Kee, F, Keinanen Kiukaanniemi, S, Ketkar, S, Kettunen, J, Khaw, K, Kiemeney, L, Kinnunen, L, Kivimaki, M, Kivmaki, M, Van der Klauw, M, Kleber, M, Knowles, J, Koenig, W, Kolcic, I, Kolovou, G, König, I, Koskinen, S, Kovacs, P, Kraft, P, Kraja, A, Kristiansson, K, Krjutåjkov, K, Kroemer, H, Krohn, J, Krzelj, V, Kuh, D, Kulzer, J, Kumari, M, Kuulasmaa, K, Kuusisto, J, Kvaloy, K, Laakso, M, Laitinen, J, Lakka, T, Lamina, C, Langenberg, C, Lantieri, O, Lathrop, G, Launer, L, Lawlor, D, Lawrence, R, Leach, I, Lecoeur, C, Lee, S, Lehtimäki, T, Leitzmann, M, Lettre, G, Levinson, D, Li, G, Li, S, Liang, L, Lin, D, Lind, L, Lindgren, C, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Loley, C, Lorentzon, M, Luben, R, Ludwig, B, Madden, P, Magnusson, P, Mangino, M, Manunta, P, Marek, D, Marre, M, Martin, N, März, W, Maschio, A, Mathieson, I, Mcardle, W, Mccaroll, S, Mccarthy, A, Mccarthy, M, Mcknight, B, Medina Gomez, C, Medland, S, Meitinger, T, Metspalu, A, van Meurs, J, Meyre, D, Midthjell, K, Mihailov, E, Milani, L, Min, J, Moebus, S, Moffatt, M, Mohlke, K, Molony, C, Monda, K, Montgomery, G, Mooser, V, Morken, M, Morris, A, Mühleisen, T, Müller Nurasyid, M, Munroe, P, Musk, A, Narisu, N, Navis, G, Neale, B, Nelis, M, Nemesh, J, Neville, M, Ngwa, J, Nicholson, G, Nieminen, M, Njølstad, I, Nohr, E, Nolte, I, North, K, Nöthen, M, Nyholt, D, O'Connell, J, Ohlsson, C, Oldehinkel, A, van Ommen, G, Ong, K, Oostra, B, Ouwehand, W, Palmer, C, Palmer, L, Palotie, A, Paré, G, Parker, A, Paternoster, L, Pawitan, Y, Pechlivanis, S, Peden, J, Pedersen, N, Pedersen, O, Pellikka, N, Peltonen, L, Penninx, B, Perola, M, Perry, J, Person, T, Peters, A, Peters, M, Pichler, I, Pietiläinen, K, Platou, C, Polasek, O, Pouta, A, Power, C, Pramstaller, P, Preuss, M, Price, J, Prokopenko, I, Province, M, Psaty, B, Purcell, S, Pütter, C, Qi, L, Quertermous, T, Radhakrishnan, A, Raitakari, O, Rauramaa, R, Rayner, N, Rehnberg, E, Rendon, A, Ridderstråle, M, Ridker, P, Ripatti, S, Rissanen, A, Rivadeneira, F, Rivolta, C, Robertson, N, Rose, L, Rudan, I, Saaristo, T, Sager, H, Salomaa, V, Samani, N, Sambrook, J, Sanders, A, Sandholt, C, Sanna, S, Saramies, J, Schadt, E, Schipf, S, Schlessinger, D, Schreiber, S, Schunkert, H, Schwarz, P, Scott, L, Shi, J, Shin, S, Shuldiner, A, Shungin, D, Signorini, S, Silander, K, Sinisalo, J, Skrobek, B, Smit, J, Smith, A, Smith, G, Snieder, H, Soranzo, N, Sørensen, T, Sovio, U, Spector, T, Speliotes, E, Stančáková, A, Stark, K, Stefansson, K, Steinthorsdottir, V, Stephens, J, Stirrups, K, Stolk, R, Strachan, D, Strawbridge, R, Stringham, H, Stumvoll, M, Surakka, I, Swift, A, Syvanen, A, Tammesoo, M, Teder Laving, M, Teslovich, T, Teumer, A, Theodoraki, E, Thomson, B, Thorand, B, Thorleifsson, G, Thorsteinsdottir, U, Timpson, N, Tönjes, A, Tregouet, D, Tremoli, E, Trip, M, Tuomi, T, Tuomilehto, J, Tyrer, J, Uda, M, Uitterlinden, A, Usala, G, Uusitupa, M, Valle, T, Vandenput, L, Vatin, V, de Vegt, F, Vermeulen, S, Viikari, J, Virtamo, J, Visscher, P, Vitart, V, Van Vliet Ostaptchouk, J, Voight, B, Vollenweider, P, Volpato, C, Völzke, H, Waeber, G, Waite, L, Wallaschofski, H, Walters, G, Wang, Z, Wareham, N, Watanabe, R, Watkins, H, Weedon, M, Welch, R, Weyant, R, Wheeler, E, White, C, Wichmann, H, Widen, E, 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E., Bolton, JL., Bonnefond, A., Bonnycastle, LL., Boomsma, DI., Borecki, IB., Bornstein, SR., Bouatia-Naji, N., Boucher, G., Bragg-Gresham, JL., Brambilla, P., Bruinenberg, M., Buchanan, TA., Buechler, C., Cadby, G., Campbell, H., Caulfield, MJ., Cavalcanti-Proença, C., Cesana, G., Chanock, SJ., Chasman, DI., Chen, YD., Chines, PS., Clegg, DJ., Coin, L., Collins, FS., Connell, JM., Cookson, W., Cooper, MN., Croteau-Chonka, DC., Cupples, LA., Cusi, D., Day, FR., Day, IN., Dedoussis, GV., Dei, M., Deloukas, P., Dermitzakis, ET., Dimas, AS., Dimitriou, M., Dixon, AL., Dörr, M., van Duijn CM., Ebrahim, S., Edkins, S., Eiriksdottir, G., Eisinger, K., Eklund, N., Elliott, P., Erbel, R., Erdmann, J., Erdos, MR., Eriksson, JG., Esko£££Tõnu£££ T., Estrada, K., Evans, DM., de Faire, U., Fall, T., Farrall, M., Feitosa, MF., Ferrario, MM., Ferreira, T., Ferrières, J., Fischer, K., Fisher, E., Fowkes, G., Fox, CS., Franke, L., Franks, PW., Fraser, RM., Frau, F., Frayling, T., Freimer, NB., Froguel, P., Fu, M., Gaget, S., Ganna, A., Gejman, PV., Gentilini, D., Geus, EJ., Gieger, C., Gigante, B., Gjesing, AP., Glazer, NL., Goddard, ME., Goel, A., Grallert, H., Gräßler, J., Grönberg, H., Groop, LC., Groves, CJ., Gudnason, V., Guiducci, C., Gustafsson, S., Gyllensten, U., Hall, AS., Hall, P., Hallmans, G., Hamsten, A., Hansen, T., Haritunians, T., Harris, TB., van der Harst, P., Hartikainen, AL., Hassanali, N., Hattersley, AT., Havulinna, AS., Hayward, C., Heard-Costa, NL., Heath, AC., Hebebrand, J., Heid, IM., den Heijer, M., Hengstenberg, C., Herzig, KH., Hicks, AA., Hingorani, A., Hinney, A., Hirschhorn, JN., Hofman, A., Holmes, CC., Homuth, G., Hottenga, JJ., Hovingh, KG., Hu, FB., Hu, YJ., Huffman, JE., Hui, J., Huikuri, H., Humphries, SE., Hung, J., Hunt, SE., Hunter, D., Hveem, K., Hyppönen, E., Igl, W., Illig, T., Ingelsson, E., Iribarren, C., Isomaa, B., Jackson, AU., Jacobs, KB., James, AL., Jansson, JO., Jarick, I., Jarvelin, MR., Jöckel, KH., Johansson£££Åsa£££ Å., Johnson, T., Jolley, J., Jørgensen, T., Jousilahti, P., Jula, A., Justice, AE., Kaakinen, M., Kähönen, M., Kajantie, E., Kanoni, S., Kao, WH., Kaplan, LM., Kaplan, RC., Kaprio, J., Kapur, K., Karpe, F., Kathiresan, S., Kee, F., Keinanen-Kiukaanniemi, SM., Ketkar, S., Kettunen, J., Khaw, KT., Kiemeney, LA., Kilpeläinen, TO., Kinnunen, L., Kivimaki, M., Kivmaki, M., Van der Klauw MM., Kleber, ME., Knowles, JW., Koenig, W., Kolcic, I., Kolovou, G., König, IR., Koskinen, S., Kovacs, P., Kraft, P., Kraja, AT., Kristiansson, K., KrjutÅjkov, K., Kroemer, HK., Krohn, JP., Krzelj, V., Kuh, D., Kulzer, JR., Kumari, M., Kutalik£££Zoltán£££ Z., Kuulasmaa, K., Kuusisto, J., Kvaloy, K., Laakso, M., Laitinen, JH., Lakka, TA., Lamina, C., Langenberg, C., Lantieri, O., Lathrop, GM., Launer, LJ., Lawlor, DA., Lawrence, RW., Leach, IM., Lecoeur, C., Lee, SH., Lehtimäki, T., Leitzmann, MF., Lettre, G., Levinson, DF., Li, G., Li, S., Liang, L., Lin, DY., Lind, L., Lindgren, CM., Lindström, J., Liu, J., Liuzzi, A., Locke, AE., Lokki, ML., Loley, C., Loos, RJ., Lorentzon, M., Luan£££Jian'an£££ J., Luben, RN., Ludwig, B., Madden, PA., Mägi, R., Magnusson, PK., Mangino, M., Manunta, P., Marek, D., Marre, M., Martin, NG., März, W., Maschio, A., Mathieson, I., McArdle, WL., McCaroll, SA., McCarthy, A., McCarthy, MI., McKnight, B., Medina-Gomez, C., Medland, SE., Meitinger, T., Metspalu, A., van Meurs JB., Meyre, D., Midthjell, K., Mihailov, E., Milani, L., Min, JL., Moebus, S., Moffatt, MF., Mohlke, KL., Molony, C., Monda, KL., Montgomery, GW., Mooser, V., Morken, MA., Morris, AD., Morris, AP., Mühleisen, TW., Müller-Nurasyid, M., Munroe, PB., Musk, AW., Narisu, N., Navis, G., Neale, BM., Nelis, M., Nemesh, J., Neville, MJ., Ngwa, JS., Nicholson, G., Nieminen, MS., Njølstad, I., Nohr, EA., Nolte, IM., North, KE., Nöthen, MM., Nyholt, DR., O'Connell, JR., Ohlsson, C., Oldehinkel, AJ., van Ommen GJ., Ong, KK., Oostra, BA., Ouwehand, WH., Palmer, CN., Palmer, LJ., Palotie, A., Paré, G., Parker, AN., Paternoster, L., Pawitan, Y., Pechlivanis, S., Peden, JF., Pedersen, NL., Pedersen, O., Pellikka, N., Peltonen, L., Penninx, B., Perola, M., Perry, JR., Person, T., Peters, A., Peters, MJ., Pichler, I., Pietiläinen, KH., Platou, CG., Polasek, O., Pouta, A., Power, C., Pramstaller, PP., Preuss, M., Price, JF., Prokopenko, I., Province, MA., Psaty, BM., Purcell, S., Pütter, C., Qi, L., Quertermous, T., Radhakrishnan, A., Raitakari, O., Randall, JC., Rauramaa, R., Rayner, NW., Rehnberg, E., Rendon, A., Ridderstråle, M., Ridker, PM., Ripatti, S., Rissanen, A., Rivadeneira, F., Rivolta, C., Robertson, NR., Rose, LM., Rudan, I., Saaristo, TE., Sager, H., Salomaa, V., Samani, NJ., Sambrook, JG., Sanders, AR., Sandholt, C., Sanna, S., Saramies, J., Schadt, EE., Scherag, A., Schipf, S., Schlessinger, D., Schreiber, S., Schunkert, H., Schwarz, PE., Scott, LJ., Shi, J., Shin, SY., Shuldiner, AR., Shungin, D., Signorini, S., Silander, K., Sinisalo, J., Skrobek, B., Smit, JH., Smith, AV., Smith, GD., Snieder, H., Soranzo, N., Sørensen, TI., Sovio, U., Spector, TD., Speliotes, EK., Stančáková, A., Stark, K., Stefansson, K., Steinthorsdottir, V., Stephens, JC., Stirrups, K., Stolk, RP., Strachan, DP., Strawbridge, RJ., Stringham, HM., Stumvoll, M., Surakka, I., Swift, AJ., Syvanen, AC., Tammesoo, ML., Teder-Laving, M., Teslovich, TM., Teumer, A., Theodoraki, EV., Thomson, B., Thorand, B., Thorleifsson, G., Thorsteinsdottir, U., Timpson, NJ., Tönjes, A., Tregouet, DA., Tremoli, E., Trip, MD., Tuomi, T., Tuomilehto, J., Tyrer, J., Uda, M., Uitterlinden, AG., Usala, G., Uusitupa, M., Valle, TT., Vandenput, L., Vatin, V., Vedantam, S., de Vegt, F., Vermeulen, SH., Viikari, J., Virtamo, J., Visscher, PM., Vitart, V., Van Vliet-Ostaptchouk JV., Voight, BF., Vollenweider, P., Volpato, CB., Völzke, H., Waeber, G., Waite, LL., Wallaschofski, H., Walters, GB., Wang, Z., Wareham, NJ., Watanabe, RM., Watkins, H., Weedon, MN., Welch, R., Weyant, RJ., Wheeler, E., White, CC., Wichmann, HE., Widen, E., Wild, SH., Willemsen, G., Willer, CJ., Wilsgaard, T., Wilson, JF., van Wingerden, S., Winkelmann, BR., Winkler, TW., Witte, DR., Witteman, JC., Wolffenbuttel, BH., Wong, A., Wood, AR., Workalemahu, T., Wright, AF., Yang, J., Yarnell, JW., Zgaga, L., Zhao, JH., Zillikens, MC., Zitting, P., and Zondervan, KT.
Subjects: Quality Control, Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, media_common.quotation_subject, quality control, GWAMAS, Control (management), Medizin, Genome-wide association study, Biology, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Software, SDG 17 - Partnerships for the Goals, Meta-Analysis as Topic, Comparable size, Quality (business), 030304 developmental biology, media_common, Protocol (science), 0303 health sciences, business.industry, Software package, Data science, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Genome-Wide Association Study/methods, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], quality control, genome-wide association meta-analyses, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Item does not contain fulltext Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.
Published: 2014

16. Defining the role of common variation in the genomic and biological architecture of adult human height

Author: Wood, Ar, Esko, T, Yang, J, Vedantam, S, Pers, Th, Gustafsson, S, Chu, Ay, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, Ml, Croteau Chonka DC, Day, Fr, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, Au, Karjalainen, J, Lo, Ks, Locke, Ae, Mägi, R, Mihailov, E, Porcu, E, Randall, Jc, Scherag, A, Vinkhuyzen, Aa, Westra, Hj, Winkler, Tw, Workalemahu, T, Zhao, Jh, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, Gb, Feenstra, B, Feitosa, Mf, Fischer, K, Fraser, Rm, Goel, A, Gong, J, Justice, Ae, Kanoni, S, Kleber, Me, Kristiansson, K, Lim, U, Lotay, V, Lui, Jc, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, Ma, Nyholt, Dr, Palmer, Cd, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, Js, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, Rj, Sung, Yj, Tanaka, T, Teumer, A, Trompet, S, van der Laan SW, van Setten, J, Van Vliet Ostaptchouk JV, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Arnlöv, J, Arscott, Gm, Bandinelli, S, Barrett, A, Bellis, C, Bennett, Aj, Berne, C, Blüher, M, Bolton, Jl, Böttcher, Y, Boyd, Ha, Bruinenberg, M, Buckley, Bm, Buyske, S, Caspersen, Ih, Chines, Ps, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, Ew, De Jong PA, Deelen, J, Delgado, G, Denny, Jc, Dhonukshe Rutten, R, Dimitriou, M, Doney, As, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, Me, Geller, F, Giedraitis, V, Go, As, Grallert, H, Grammer, Tb, Gräßler, J, Grönberg, H, de Groot LC, Groves, Cj, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hannemann, A, Hartman, Ca, Hassinen, M, Hayward, C, Heard Costa NL, Helmer, Q, Hemani, G, Henders, Ak, Hillege, Hl, Hlatky, Ma, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat JJ, Illig, T, Isaacs, A, James, Al, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, An, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, Pk, Mahajan, A, Maillard, M, Mcardle, Wl, Mckenzie, Ca, 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M., Isotope Research, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Research Institute for Asthma and COPD (GRIAC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Ehret, Georg Benedikt, Wood, A, Esko, T, Yang, J, Vedantam, S, Pers, T, Gustafsson, S, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Fehrmann, R, Ferreira, T, Jackson, A, Karjalainen, J, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Westra, H, Winkler, T, 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Schoor N.M., Van Der Velde N., Van Heemst D., Van Oort F.V.A., Vermeulen S.H., Verweij N., Vonk J.M., Waite L.L., Waldenberger M., Wennauer R., Wilkens L.R., Willenborg C., Wilsgaard T., Wojczynski M.K., Wong A., Wright A.F., Zhang Q., Arveiler D., Bakker S.J.L., Beilby J., Bergman R.N., Bergmann S., Biffar R., Blangero J., Boomsma D.I., Bornstein S.R., Bovet P., Brambilla P., Brown M.J., Campbell H., Caulfield M.J., Chakravarti A., Collins R., Collins F.S., Crawford D.C., Cupples L.A., Danesh J., De Faire U., Den Ruijter H.M., Erbel R., Erdmann J., Eriksson J.G., Farrall M., Ferrannini E., Ferrieres J., Ford I., Forouhi N.G., Forrester T., Gansevoort R.T., Gejman P.V., Gieger C., Golay A., Gottesman O., Gudnason V., Gyllensten U., Haas D.W., Hall A.S., Harris T.B., Hattersley A.T., Heath A.C., Hengstenberg C., Hicks A.A., Hindorff L.A., Hingorani A.D., Hofman A., Hovingh G.K., Humphries S.E., Hunt S.C., Hypponen E., Jacobs K.B., Jarvelin M.-R., Jousilahti P., Jula A.M., Kaprio J., Kastelein J.J.P., Kayser M., Kee F., Keinanen-Kiukaanniemi S.M., Kiemeney L.A., Kooner J.S., Kooperberg C., Koskinen S., Kovacs P., Kraja A.T., Kumari M., Kuusisto J., Lakka T.A., Langenberg C., Le Marchand L., Lehtimaki T., Lupoli S., Madden P.A.F., Mannisto S., Manunta P., Marette A., Matise T.C., McKnight B., Meitinger T., Moll F.L., Montgomery G.W., Morris A.D., Morris A.P., Murray J.C., Nelis M., Ohlsson C., Oldehinkel A.J., Ong K.K., Ouwehand W.H., Pasterkamp G., Peters A., Pramstaller P.P., Price J.F., Qi L., Raitakari O.T., Rankinen T., Rao D.C., Rice T.K., Ritchie M., Rudan I., Salomaa V., Samani N.J., Saramies J., Sarzynski M.A., Schwarz P.E.H., Sebert S., Sever P., Shuldiner A.R., Sinisalo J., Steinthorsdottir V., Stolk R.P., Tardif J.-C., Tonjes A., Tremblay A., Tremoli E., Virtamo J., Vohl M.-C., Amouyel P., Asselbergs F.W., Assimes T.L., Bochud M., Boehm B.O., Boerwinkle E., Bottinger E.P., Bouchard C., Cauchi S., Chambers J.C., Chanock S.J., Cooper R.S., De Bakker P.I.W., Dedoussis G., Ferrucci L., Franks P.W., Froguel P., Groop L.C., Haiman C.A., Hamsten A., Hayes M.G., Hui J., Hunter D.J., Hveem K., Jukema J.W., Kaplan R.C., Kivimaki M., Kuh D., Laakso M., Liu Y., Martin N.G., Marz W., Melbye M., Moebus S., Munroe P.B., Njolstad I., Oostra B.A., Palmer C.N.A., Pedersen N.L., Perola M., Perusse L., Peters U., Powell J.E., Power C., Quertermous T., Rauramaa R., Reinmaa E., Ridker P.M., Rivadeneira F., Rotter J.I., Saaristo T.E., Saleheen D., Schlessinger D., Slagboom P.E., Snieder H., Spector T.D., Strauch K., Stumvoll M., Tuomilehto J., Uusitupa M., Van Der Harst P., Volzke H., Walker M., Wareham N.J., Watkins H., Wichmann H.-E., Wilson J.F., Zanen P., Deloukas P., Heid I.M., Lindgren C.M., Mohlke K.L., Speliotes E.K., Thorsteinsdottir U., Barroso I., Fox C.S., North K.E., Strachan D.P., Beckmann J.S., Berndt S.I., Boehnke M., Borecki I.B., McCarthy M.I., Metspalu A., Stefansson K., Uitterlinden A.G., Van Duijn C.M., Franke L., Willer C.J., Price A.L., Lettre G., Loos R.J.F., Weedon M.N., Ingelsson E., O'Connell J.R., Abecasis G.R., Chasman D.I., Goddard M.E., Visscher P.M., Hirschhorn J.N., and Frayling T.M.
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Electronic Medical Records and Genomics (eMEMERGEGE) Consortium, Medizin, Genome-wide association study, Adult, Analysis of Variance, Body Height/genetics, European Continental Ancestry Group/genetics, Genetic Variation/genetics, Genetics, Population, Genome-Wide Association Study/methods, Humans, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide/genetics, heritability, 0302 clinical medicine, Genome-wide, SNPS, snps, Genetics & Heredity, ddc:616, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, variants, GENETIC-VARIATION, Biological Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], body height, genetic-variation, Life Sciences & Biomedicine, Single Nucleotide/genetics, Human, European Continental Ancestry Group, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, NO, complex traits, 03 medical and health sciences, Genetic variation, heritability, adult, height, Polymorphism, Human height, PAGEGE Consortium, education, Gene, VLAG, 030304 developmental biology, Global Nutrition, Wereldvoeding, genome-wide association study, Science & Technology, Whites, Oligonucleotide Array Sequence Analysi, MUTATIONS, COMPLEX TRAITS, ta1184, Klinisk medicin, population genetics, Genetic Variation, Heritability, ta3121, mutations, Genetic architecture, Body Height, genetic variation, MIGen Consortium, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Clinical Medicine, 030217 neurology & neurosurgery, height, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract: Item does not contain fulltext Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Published: 2014

17. Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

Author: Bigdeli, T. B, Ripke, S, Bacanu, Sa, Lee, S. H, Wray, Nr, Gejman, P. V, Rietschel, M, Cichon, S, St Clair, D, Corvin, A, Kirov, G, Mcquillin, A, Gurling, H, Rujescu, D, Andreassen, O. A, Werge, T, Blackwood, D. H. R, Pato, C. N, Pato, M. T, Malhotra, A. K, O'Donovan, M. C, Kendler, K. S, Fanous, A. H, Neale, Bm, Walters, Jt, Farh, Kh, Holmans, Pa, Lee, P, Bulik Sullivan, B, Collier, Da, Huang, H, Pers, Th, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Begemann, M, Belliveau, Ra, Bene, J, Bergen, Se, Bevilacqua, E, Bigdeli, Tb, Black, Dw, Børglum, Ad, Bruggeman, R, Buccola, Ng, Buckner, Rl, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, Rm, Carr, Vj, Carrera, N, Catts, Sv, Chambert, Kd, Chan, Rc, Chen, Ry, Chen, Ey, Cheng, W, Cheung, Ef, Chong, Sa, Cloninger, C, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, Jj, Curtis, D, Davidson, M, Davis, Kl, Degenhardt, F, Del, Favero, J, Delisi, Le, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott Price, V, Essioux, L, Fanous, Ah, Farrell, Ms, Frank, J, Franke, L, Freedman, R, Freimer, Nb, Friedl, M, Friedman, Ji, Fromer, M, Genovese, G, Georgieva, L, Gershon, Es, Giegling, I, Giusti Rodríguez, P, Godard, S, Goldstein, Ji, Golimbet, V, Gopal, S, Gratten, J, Grove, J, Haan, De, L, Hammer, C, Hamshere, Ml, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, Am, Henskens, Fa, Herms, S, Hirschhorn, Jn, Hoffmann, P, Hofman, A, Hollegaard, Mv, Hougaard, Dm, Ikeda, M, Joa, I, Julìa, A, Kahn, Rs, Kalaydjieva, L, Karachanak Yankova, S, Karjalainen, J, Kavanagh, D, Keller, Mc, Kelly, Bj, Kennedy, Jl, Khrunin, A, Kim, Y, Klovins, J, Knowles, Ja, Konte, B, Kucinskas, V, Kucinskiene, Za, Kuzelova Ptackova, H, Kähler, Ak, Laurent, C, Keong, Jl, Lee, S, Legge, Se, Lerer, B, Li, M, Li, T, Liang, Ky, Lieberman, J, Limborska, S, Loughland, Cm, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, Pk, Maher, Bs, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, Mccarley, Rw, Mcdonald, C, Mcintosh, Am, Meier, S, Meijer, Cj, Melegh, B, Melle, I, Mesholam Gately, Ri, Metspalu, A, Michie, Pt, Milani, L, Milanova, V, Mokrab, Y, Morris, Dw, Mors, O, Mortensen, Pb, Murphy, Kc, Murray, Rm, Myin Germeys, I, Müller Myhsok, B, Nelis, M, Nenadic, I, Nertney, Da, Nestadt, G, Nicodemus, Kk, Nikitina Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, F, Sy, Oh, Olincy, A, Olsen, L, Jv, Os, Pantelis, C, Papadimitriou, Gn, Papiol, S, Parkhomenko, E, Pato, Mt, Paunio, T, Pejovic Milovancevic, M, Perkins, Do, Pietiläinen, O, Pimm, J, Pocklington, Aj, Powell, J, Price, A, Pulver, Ae, Purcell, Sm, Quested, D, Rasmussen, Hb, Reichenberg, A, Reimers, Ma, Richards, Al, Roffman, Jl, Roussos, P, Ruderfer, Dm, Salomaa, V, Sanders, Ar, Schall, U, Schubert, Cr, Schulze, Tg, Schwab, Sg, Scolnick, Em, Scott, Rj, Seidman, Lj, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, Jm, Sim, K, Slominsky, P, Smoller, Jw, Hc, So, Spencer, Cc, Stahl, Ea, Stefansson, H, Steinberg, S, Stogmann, E, Straub, Re, Strengman, E, Strohmaier, J, Stroup, T, Subramaniam, M, Suvisaari, J, Svrakic, Dm, Szatkiewicz, Jp, Söderman, E, Thirumalai, S, Toncheva, D, Tooney, Pa, Tosato, Sarah, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, Bt, Weiser, M, Wildenauer, Db, Williams, Nm, Williams, S, Witt, Sh, Wolen, Ar, Wong, Eh, Wormley, Bk, Jq, Wu, Hs, Xi, Zai, Cc, Zheng, X, Zimprich, F, Stefansson, K, Visscher, Pm, Adolfsson, R, Andreassen, Oa, Blackwood, Dh, Bramon, E, Buxbaum, Jd, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, Pv, Gill, M, Hultman, Cm, Iwata, N, Jablensky, Av, Jönsson, Eg, Kendler, Ks, Knight, J, Lencz, T, Levinson, Df, Qs, Li, Liu, J, Malhotra, Ak, Mccarroll, Sa, Moran, Jl, Mowry, Bj, Nöthen, Mm, Ophoff, Ra, Owen, Mj, Palotie, A, Pato, Cn, Petryshen, Tl, Posthuma, D, Riley, Bp, Sham, Pc, Sklar, P, Clair, Ds, Weinberger, Dr, Wendland, Jr, Daly, Mj, Sullivan, Pf, O'Donovan, Mc, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Bigdeli, Tim B, Ripke, Stephan, Bacanu, Silviu-Alin, Lee, Sang Hong, Fanous, Ayman H, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotype International Consortium, Wellcome Trust Case-Control Consortium 2, Other departments, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), and Del-Favero, Jurgen
Subjects: 0301 basic medicine, Multifactorial Inheritance, Bipolar Disorder, Inheritance Patterns, Genome-wide association study, Single-nucleotide polymorphism, polygenic, heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, SNP, GWAS, Family, Genetic Predisposition to Disease, Family history, Allele, Genetics (clinical), Genetic association, Genetics & Heredity, Psychiatry, Genetics, Depressive Disorder, Major, family history, Models, Genetic, Case-control study, medicine.disease, 3. Good health, schizophrenia, Psychiatry and Mental health, 030104 developmental biology, Schizophrenia, Case-Control Studies, Human medicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R-2=0.0021; P=0.00331; P-value threshold
Published: 2016

18. Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Author: Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Aloso, R, Raybould, R, Chen, Y, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, L, Bacq, D, Denning, N, Jian, X, Zhao, Y, Zompo, MD, Fox, NC, Grove, ML, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Garcia, FS, Patel, Y, Brody, JA, Dombroski, B, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewics, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, W, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Pichler, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Fernadez, CM, Sussams, R, Lin, H, Fairchild, TJ, Benito, YA, Holmes, C, Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roschupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernández, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth Jr, WT, Montine, TJ, Frisardi, V, Ortega-Cubero, S, Rivadeneira, F, Petersen, RC, Deramecourt, V, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Caltagirone, C, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AG, Royall, DR, Dufouil, C, Maletta, RG, Moreno-Grau, S, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Baldwin, CT, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frölich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JI, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, C, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Cribbs, DH, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hüll, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, G, Jin, LW, Leonenko, G, Jun, G, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jöckel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nöthen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, McKee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O’Bryant, S, Coto, E, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, W, Mead, S, Peskind, E, Rosser, M, Pierce, A, Ryan, N, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Bossù, P, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Crane, PK, Bennett, DA, Boccardi, V, De Jager, PL, Warner, N, Lopez, OL, McDonough, S, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O’Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ruiz, A, Ramirez, A, Wang, LS, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, Bis, JC [0000-0002-3409-1110], Garnier, JG [0000-0003-4991-763X], Smith, AV [0000-0001-9088-234X], Denning, N [0000-0001-8467-7382], Vandenberghe, R [0000-0001-6237-2502], Himali, JJ [0000-0003-1391-9481], Rodriguez-Rodriguez, E [0000-0001-7742-677X], Frisardi, V [0000-0003-0764-7387], Ortega-Cubero, S [0000-0003-0520-9439], Hanon, O [0000-0002-4697-122X], Brice, A [0000-0002-0941-3990], Albin, RL [0000-0002-0629-608X], Buxbaum, JD [0000-0001-8898-8313], Bass, NJ [0000-0002-4481-778X], Fisher, E [0000-0003-2850-9936], Bayer, A [0000-0002-7514-248X], Gallacher, J [0000-0002-2394-5299], Brayne, C [0000-0001-5307-663X], Riedel-Heller, S [0000-0003-4321-6090], Al-Chalabi, A [0000-0002-4924-7712], and Apollo - University of Cambridge Repository
Subjects: Aging, 4202 Epidemiology, Genome-wide association study, Disease, Neurodegenerative, Biology, 3101 Biochemistry and Cell Biology, Alzheimer's Disease, 3105 Genetics, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Acquired Cognitive Impairment, Genetics, medicine, 2.1 Biological and endogenous factors, Dementia, Gene, 030304 developmental biology, Genetic association, 2 Aetiology, 0303 health sciences, Prevention, Human Genome, 42 Health Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Lipid metabolism, medicine.disease, Brain Disorders, 3. Good health, Meta-analysis, Neurological, Alzheimer's disease, 030217 neurology & neurosurgery, 31 Biological Sciences
Abstract: IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.
Published: 2018
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19. Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Author: Sud, A, Thomsen, H, Law, PJ, Försti, A, da Silva Filho, MI, Holroyd, A, Broderick, P, Orlando, G, Lenive, O, Wright, L, Cooke, R, Easton, D, Pharaoh, P, Dunning, A, Peto, J, Canzian, F, Eeles, R, Kote-Jarai, S, Muir, K, Pashayan, N, the PRACTICAL consortium, Hoffman, P, Nöthen, MM, Jöckel, K-H, von Strandmann, EP, Lightfoot, T, Kane, E, Roman, E, Lake, A, Montgomery, D, Jarrett, RF, Swerdlow, AJ, Engert, A, Orr, N, Hemminki, K, Houlston, RS, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository
Subjects: Humans, Genetic Predisposition to Disease, Hodgkin Disease, Polymorphism, Single Nucleotide, Alleles, HLA-DP beta-Chains, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Several susceptibility loci for classical Hodgkin lymphoma (cHL) have been reported, however much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies (GWAS), a new GWAS, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all cHL at 6q22.33 (rs9482849, P=1.52 × 10-8) and for nodular sclerosis HL (NSHL) at 3q28 (rs4459895, P=9.43 × 10-17), 6q23.3 (rs6928977, P=4.62 × 10-55 11), 10p14 (rs3781093, P=9.49 × 10-13), 13q34 (rs112998813, P=4.58 × 10-8) and 16p13.13 (rs34972832, P=2.12 × 10-8). Additionally, independent loci within the HLA region are observed for NSHL (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity HL (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.
Published: 2017

20. The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders

Author: Chang, H, Hoshina, N, Zhang, C, Ma, Y, Cao, H, Wang, Y, Wu, DD, Bergen, SE, Landén, M, Hultman, CM, Preisig, M, Kutalik, Z, Castelao, E, Grigoroiu-Serbanescu, M, Forstner, AJ, Strohmaier, J, Hecker, J, Schulze, TG, Müller-Myhsok, B, Reif, A, Mitchell, PB, Martin, NG, Schofield, PR, Cichon, S, Nöthen, MM, Walter, H, Erk, S, Heinz, A, Amin, N, Van Duijn, CM, Meyer-Lindenberg, A, Tost, H, Xiao, X, Yamamoto, T, Rietschel, M, Li, M, Backlund, L, Frisén, L, Lavebratt, C, Schalling, M, Ösby, U, Mühleisen, TW, Leber, M, Degenhardt, F, Treutlein, J, Mattheisen, M, Maaser, A, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Streit, F, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Wright, A, Fullerton, JM, Montgomery, GW, Medland, SE, Gordon, SD, Becker, T, Schumacher, J, Propping, P, Chang, H, Hoshina, N, Zhang, C, Ma, Y, Cao, H, Wang, Y, Wu, DD, Bergen, SE, Landén, M, Hultman, CM, Preisig, M, Kutalik, Z, Castelao, E, Grigoroiu-Serbanescu, M, Forstner, AJ, Strohmaier, J, Hecker, J, Schulze, TG, Müller-Myhsok, B, Reif, A, Mitchell, PB, Martin, NG, Schofield, PR, Cichon, S, Nöthen, MM, Walter, H, Erk, S, Heinz, A, Amin, N, Van Duijn, CM, Meyer-Lindenberg, A, Tost, H, Xiao, X, Yamamoto, T, Rietschel, M, Li, M, Backlund, L, Frisén, L, Lavebratt, C, Schalling, M, Ösby, U, Mühleisen, TW, Leber, M, Degenhardt, F, Treutlein, J, Mattheisen, M, Maaser, A, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Streit, F, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Wright, A, Fullerton, JM, Montgomery, GW, Medland, SE, Gordon, SD, Becker, T, Schumacher, J, and Propping, P
Abstract: Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Published: 2018

21. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

Author: Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O'Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O'Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, and Turecki, G
Abstract: IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%
Published: 2018

22. Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder

Author: Mühleisen, TW, Reinbold, CS, Forstner, AJ, Abramova, LI, Alda, M, Babadjanova, G, Bauer, M, Brennan, P, Chuchalin, A, Cruceanu, C, Czerski, PM, Degenhardt, F, Fischer, SB, Fullerton, JM, Gordon, SD, Grigoroiu-Serbanescu, M, Grof, P, Hauser, J, Hautzinger, M, Herms, S, Hoffmann, P, Kammerer-Ciernioch, J, Khusnutdinova, E, Kogevinas, M, Krasnov, V, Lacour, A, Laprise, C, Leber, M, Lissowska, J, Lucae, S, Maaser, A, Maier, W, Martin, NG, Mattheisen, M, Mayoral, F, McKay, JD, Medland, SE, Mitchell, PB, Moebus, S, Montgomery, GW, Müller-Myhsok, B, Oruc, L, Pantelejeva, G, Pfennig, A, Pojskic, L, Polonikov, A, Reif, A, Rivas, F, Rouleau, GA, Schenk, LM, Schofield, PR, Schwarz, M, Streit, F, Strohmaier, J, Szeszenia-Dabrowska, N, Tiganov, AS, Treutlein, J, Turecki, G, Vedder, H, Witt, SH, Schulze, TG, Rietschel, M, Nöthen, MM, Cichon, S, Mühleisen, TW, Reinbold, CS, Forstner, AJ, Abramova, LI, Alda, M, Babadjanova, G, Bauer, M, Brennan, P, Chuchalin, A, Cruceanu, C, Czerski, PM, Degenhardt, F, Fischer, SB, Fullerton, JM, Gordon, SD, Grigoroiu-Serbanescu, M, Grof, P, Hauser, J, Hautzinger, M, Herms, S, Hoffmann, P, Kammerer-Ciernioch, J, Khusnutdinova, E, Kogevinas, M, Krasnov, V, Lacour, A, Laprise, C, Leber, M, Lissowska, J, Lucae, S, Maaser, A, Maier, W, Martin, NG, Mattheisen, M, Mayoral, F, McKay, JD, Medland, SE, Mitchell, PB, Moebus, S, Montgomery, GW, Müller-Myhsok, B, Oruc, L, Pantelejeva, G, Pfennig, A, Pojskic, L, Polonikov, A, Reif, A, Rivas, F, Rouleau, GA, Schenk, LM, Schofield, PR, Schwarz, M, Streit, F, Strohmaier, J, Szeszenia-Dabrowska, N, Tiganov, AS, Treutlein, J, Turecki, G, Vedder, H, Witt, SH, Schulze, TG, Rietschel, M, Nöthen, MM, and Cichon, S
Abstract: Background Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci. Methods We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan. Results Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system. Limitations Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients. Conclusions Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD.
Published: 2018

23. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author: Ni, G, Gratten, J, Wray, NR, Lee, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Haan, L de, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Juliá, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kähler, AK, Laurent, C, Keong, JLC, Legge, SE, Lerer, B, Li, M, Li, T, Liang, KY, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, SY, Olincy, A, Olsen, L, van Os, JV, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, HC, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, Xuebin, Zimprich, F, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Børglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, Daniëlle, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Clair, DS, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, O'Donovan, MC, Ni, G, Gratten, J, Wray, NR, Lee, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Haan, L de, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Juliá, A, Kahn, RS, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kähler, AK, Laurent, C, Keong, JLC, Legge, SE, Lerer, B, Li, M, Li, T, Liang, KY, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lönnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Müller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, SY, Olincy, A, Olsen, L, van Os, JV, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, HC, Spencer, CCA, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Söderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, Xuebin, Zimprich, F, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Børglum, AD, Cichon, S, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, Daniëlle, Rietschel, M, Riley, BP, Rujescu, D, Sham, PC, Clair, DS, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, and O'Donovan, MC
Published: 2018

24. Variability in Working Memory Performance Explained by Epistasis vs Polygenic Scores in the ZNF804A Pathway

Author: Nicodemus, Kk, Hargreaves, A, Morris, D, Anney, R, Gill, M, Corvin, A, Donohoe, G, Ripke, S, Sanders, Ar, Kendler, Ks, Levinson, Df, Sklar, P, Holmans, Pa, Lin, Dy, Duan, J, Ophoff, Ra, Andreassen, Oa, Scolnick, E, Cichon, S, Clair, St, D, Gurling, H, Werge, T, Rujescu, D, Blackwood, Dh, Pato, Cn, Malhotra, Ak, Purcell, S, Dudbridge, F, Neale, Bm, Rossin, L, Visscher, Pm, Posthuma, D, Ruderfer, Dm, Fanous, A, Stefansson, H, Steinberg, S, Mowry, Bj, Golimbet, V, Hert, De, M, Jönsson, Eg, Bitter, I, Pietiläinen, Op, Collier, Da, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, Rl, Amin, F, Bass, N, Bergen, Se, Black, Dw, Børglum, Ad, Brown, Ma, Bruggeman, R, Buccola, Ng, Byerley, Wf, Cahn, W, Cantor, Rm, Carr, Vj, Catts, Sv, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, Pa, Datta, S, Haan, De, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Duong, L, Dwyer, S, Fink Jensen, A, Freedman, R, Freimer, Nb, Friedl, M, Georgieva, L, Giegling, I, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, Am, Henskens, Fa, Hougaard, Dm, Hultman, Cm, Ingason, A, Jablensky, Av, Jakobsen, Kd, Jay, M, Jürgens, G, Kahn, Rs, Keller, Mc, Kenis, G, Kenny, E, Kim, Y, Kirov, Gk, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, Vk, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, Ky, Lichtenstein, P, Lieberman, Ja, Linszen, Dh, Lönnqvist, J, Loughland, Cm, Maclean, Aw, Maher, Bs, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, Ka, Mcgrath, Jj, Mcintosh, A, Mclean, De, Mcquillin, A, Melle, I, Michie, Pt, Milanova, V, Morris, Dw, Mors, O, Mortensen, Pb, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, Da, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nöthen, Mm, O'Dushlaine, Ct, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, Tf, Owen, Mj, Pantelis, C, Papadimitriou, G, Pato, Mt, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, Ae, Puri, V, Quested, D, Quinn, Em, Rasmussen, Hb, Réthelyi, Jm, Ribble, R, Rietschel, M, Riley, Bp, Ruggeri, Mirella, Schall, U, Schulze, Tg, Schwab, Sg, Scott, Rj, Shi, J, Sigurdsson, E, Silverman, Jm, Spencer, Cc, Stefansson, K, Strange, A, Strengman, E, Stroup, T, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, Jh, Timm, S, Toncheva, D, Van, Den, Oord, E, Van, Os, Van, J, Winkel, R, Veldink, J, Walsh, D, Wang, Ag, Wiersma, D, Wildenauer, Db, Williams, Hj, Williams, Nm, Wormley, B, Zammit, S, Sullivan, Pf, O'Donovan, Mc, Daly, Mj, Gejman, P., Functional Genomics, Complex Trait Genetics, De Hert, Marc, Myin-Germeys, Inez, van Winkel, Ruud, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, Amsterdam Neuroscience, and Adult Psychiatry
Subjects: epistasis, Male, Multifactorial Inheritance, polygenic, Neuropsychological Tests, involvement, 0302 clinical medicine, Neural Pathways, 2.1 Biological and endogenous factors, Psychology, schizophrenia risk, psychosis variant, Aetiology, 0303 health sciences, susceptibility gene znf804a, medicine.diagnostic_test, phenotypes, Zinc Fingers, Neuropsychological test, Single Nucleotide, Middle Aged, Serious Mental Illness, Psychiatry and Mental health, Memory, Short-Term, Mental Health, Schizophrenia, Major depressive disorder, Female, Cognitive Sciences, social and economic factors, Adult, medicine.medical_specialty, Psychosis, working memory, schizophrenia, IQ, Schizoaffective disorder, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene interaction, Genetic, Social cognition, Memory, Clinical Research, 2.3 Psychological, Behavioral and Social Science, medicine, Genetics, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, Psychiatry, 030304 developmental biology, Other Medical and Health Sciences, Prevention, Wellcome Trust Case Control Consortium 2, Neurosciences, Genetic Variation, Epistasis, Genetic, Schizophrenia Psychiatric Genome-wide Association Study (GWAS) Consortium, medicine.disease, attention, Brain Disorders, deficits, Short-Term, Psychotic Disorders, genome-wide association, Epistasis, healthy controls, identification, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score. © 2014 American Medical Association. All rights reserved.
Published: 2014

25. Biological interpretation of genome-wide association studies using predicted gene functions

Author: Pers TH, Karjalainen JM, Chan Y, Westra HJ, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, Frayling T, Speliotes EK, Boehnke M, Raychaudhuri S, Fehrmann RS, Hirschhorn JN, Franke L, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Mägi R, Mihailov E, Porcu E, Randall JC, Scherag A, Vinkhuyzen AA, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice E, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Mateo Leach I, Medina Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Ärnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Bolton JL, Böttcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Chines PS, Clarke R, Claudi Boehm S, Cooper M, Daw EW, De Jong A, Deelen J, Delgado G, Denny JC, Dhonukshe Rutten R, Dimitriou M, Doney AS, Dörr M, Eklund N, Eury E, Folkersen L, Garcia ME, Geller F, Giedraitis V, Go AS, Grallert H, Grammer TB, Gräßler J, Grönberg H, de Groot LC, Groves CJ, Haessler J, Haller T, Hallmans G, Hannemann A, Hartman CA, Hassinen M, Hayward C, Heard Costa NL, Helmer Q, Hemani G, Henders AK, Hillege HL, Hlatky MA, Hoffmann W, Hoffmann P, Holmen O, Houwing Duistermaat JJ, Illig T, Isaacs A, James AL, Jeff J, Johansen B, Johansson Å, Jolley J, Juliusdottir T, Junttila J, Kho AN, Kinnunen L, Klopp N, Kocher T, Kratzer W, Lichtner P, Lind L, Lindström J, Lobbens S, Lorentzon M, Lu Y, Lyssenko V, Magnusson PK, Mahajan A, Maillard M, McArdle WL, McKenzie CA, McLachlan S, McLaren PJ, Menni C, Merger S, Milani L, Moayyeri A, Monda KL, Morken MA, Müller G, Müller Nurasyid M, Musk AW, Narisu N, Nauck M, Nolte IM, Nöthen MM, Oozageer L, Pilz S, Rayner NW, Renstrom F, Robertson NR, Rose LM, Roussel R, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Schunkert H, Scott RA, Sehmi J, Seufferlein T, Shi J, Silventoinen K, Smit JH, Smith AV, Smolonska J, Stanton AV, Stirrups K, Stott DJ, Stringham HM, Sundström J, Swertz MA, Syvänen AC, Tayo BO, Thorleifsson G, Tyrer JP, van Dijk S, van Schoor NM, van der Velde N, van Heemst D, van Oort FV, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Waldenberger M, Wennauer R, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Arveiler D, Bakker SJ, Beilby J, Bergman RN, Bergmann S, Biffar R, Blangero J, Boomsma I, Bornstein SR, Bovet P, BRAMBILLA, PAOLO, Brown MJ, Campbell H, Caulfield MJ, Chakravarti A, Collins R, Collins FS, Crawford DC, Cupples LA, Danesh J, de Faire U, den Ruijter HM, Erbel R, Erdmann J, Eriksson JG, Farrall M, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Gansevoort RT, Gejman PV, Gieger C, Golay A, Gottesman O, Gudnason V, Gyllensten U, Haas DW, Hall AS, Harris TB, Hattersley AT, Heath AC, Hengstenberg C, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Jacobs KB, Jarvelin MR, Jousilahti P, Jula AM, Kaprio J, Kastelein JJ, Kayser M, Kee F, Keinanen Kiukaanniemi SM, Kiemeney LA, Kooner JS, Kooperberg C, Koskinen S, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lupoli S, Madden PA, Männistö S, Manunta P, Marette A, Matise TC, McKnight B, Meitinger T, Moll FL, Montgomery GW, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Ouwehand WH, Pasterkamp G, Peters A, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ritchie M, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schwarz PE, Sebert S, Sever P, Shuldiner AR, Sinisalo J, Steinthorsdottir V, Stolk RP, Tardif JC, Tönjes A, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PI, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hayes MG, Hui J, Hunter DJ, Hveem K, Jukema JW, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Powell JE, Power C, Quertermous T, Rauramaa R, Reinmaa E, Ridker PM, Rivadeneira F, Rotter JI, Saaristo TE, Saleheen D, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Strauch K, Stumvoll M, Tuomilehto J, Uusitupa M, van der Harst P, Völzke H, Walker M, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Zanen P, Deloukas P, Heid IM, Lindgren CM, Mohlke KL, Thorsteinsdottir U, Barroso I, Fox CS, North KE, Strachan DP, Beckmann JS, Berndt SI, Borecki IB, McCarthy MI, Metspalu A, Stefansson K, Uitterlinden AG, van Duijn CM, Willer CJ, Price AL, Lettre G, Loos RJ, Weedon MN, Ingelsson E, O'Connell JR, Abecasis GR, Chasman DI, Goddard ME, Visscher PM, Frayling T.M., Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Wood, AR., Esko, T., Yang, J., Vedantam, S., Pers, TH., Gustafsson, S., Chu, AY., Estrada, K., Luan£££Jian'an£££ J., Kutalik£££Zoltán£££ Z., Amin, N., Buchkovich, ML., Croteau-Chonka, DC., Day, FR., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, AU., Karjalainen, J., Lo, KS., Locke, AE., Mägi, R., Mihailov, E., Porcu, E., Randall, JC., Scherag, A., Vinkhuyzen, AA., Westra, HJ., Winkler, TW., Workalemahu, T., Zhao, JH., Absher, D., Albrecht, E., 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Garcia, ME., Geller, F., Giedraitis, V., Go, AS., Grallert, H., Grammer, TB., Gräßler, J., Grönberg, H., de Groot LC., Groves, CJ., Haessler, J., Haller, T., Hallmans, G., Hannemann, A., Hartman, CA., Hassinen, M., Hayward, C., Heard-Costa, NL., Helmer, Q., Hemani, G., Henders, AK., Hillege, HL., Hlatky, MA., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, JJ., Illig, T., Isaacs, A., James, AL., Jeff, J., Johansen, B., Johansson£££Åsa£££ Å., Jolley, J., Juliusdottir, T., Junttila, J., Kho, AN., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, PK., Mahajan, A., Maillard, M., McArdle, WL., McKenzie, CA., McLachlan, S., McLaren, PJ., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, KL., Morken, MA., Müller, G., Müller-Nurasyid, M., Musk, AW., Narisu, N., Nauck, M., Nolte, IM., Nöthen, MM., Oozageer, L., Pilz, S., Rayner, NW., Renstrom, F., Robertson, NR., Rose, LM., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, FR., Schunkert, H., Scott, RA., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, JH., Smith, AV., Smolonska, J., Stanton, AV., Stirrups, K., Stott, DJ., Stringham, HM., Sundström, J., Swertz, MA., Syvänen, AC., Tayo, BO., Thorleifsson, G., Tyrer, JP., van Dijk, S., van Schoor NM., van der Velde, N., van Heemst, D., van Oort FV., Vermeulen, SH., Verweij, N., Vonk, JM., Waite, LL., Waldenberger, M., Wennauer, R., Wilkens, LR., Willenborg, C., Wilsgaard, T., Wojczynski, MK., Wong, A., Wright, AF., Zhang, Q., Arveiler, D., Bakker, SJ., Beilby, J., Bergman, RN., Bergmann, S., Biffar, R., Blangero, J., Boomsma, I., Bornstein, SR., Bovet, P., Brambilla, P., Brown, MJ., Campbell, H., Caulfield, MJ., Chakravarti, A., Collins, R., Collins, FS., Crawford, DC., Cupples, LA., Danesh, J., de Faire, U., den Ruijter HM., Erbel, R., Erdmann, J., Eriksson, JG., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, NG., Forrester, T., Gansevoort, RT., Gejman, PV., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, DW., Hall, AS., Harris, TB., Hattersley, AT., Heath, AC., Hengstenberg, C., Hicks, AA., Hindorff, LA., Hingorani, AD., Hofman, A., Hovingh, GK., Humphries, SE., Hunt, SC., Hypponen, E., Jacobs, KB., Jarvelin, MR., Jousilahti, P., Jula, AM., Kaprio, J., Kastelein, JJ., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, SM., Kiemeney, LA., Kooner, JS., Kooperberg, C., Koskinen, S., Kovacs, P., Kraja, AT., Kumari, M., Kuusisto, J., Lakka, TA., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, PA., Männistö, S., Manunta, P., Marette, A., Matise, TC., McKnight, B., Meitinger, T., Moll, FL., Montgomery, GW., Morris, AD., Morris, AP., Murray, JC., Nelis, M., Ohlsson, C., Oldehinkel, AJ., Ong, KK., Ouwehand, WH., Pasterkamp, G., Peters, A., Pramstaller, PP., Price, JF., Qi, L., Raitakari, OT., Rankinen, T., Rao, DC., Rice, TK., Ritchie, M., Rudan, I., Salomaa, V., Samani, NJ., Saramies, J., Sarzynski, MA., Schwarz, PE., Sebert, S., Sever, P., Shuldiner, AR., Sinisalo, J., Steinthorsdottir, V., Stolk, RP., Tardif, JC., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, MC., Amouyel, P., Asselbergs, FW., Assimes, TL., Bochud, M., Boehm, BO., Boerwinkle, E., Bottinger, EP., Bouchard, C., Cauchi, S., Chambers, JC., Chanock, SJ., Cooper, RS., de Bakker PI., Dedoussis, G., Ferrucci, L., Franks, PW., Froguel, P., Groop, LC., Haiman, CA., Hamsten, A., Hayes, MG., Hui, J., Hunter, DJ., Hveem, K., Jukema, JW., Kaplan, RC., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, NG., März, W., Melbye, M., Moebus, S., Munroe, PB., Njølstad, I., Oostra, BA., Palmer, CN., Pedersen, NL., Perola, M., Pérusse, L., Peters, U., Powell, JE., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, PM., Rivadeneira, F., Rotter, JI., Saaristo, TE., Saleheen, D., Schlessinger, D., Slagboom, PE., Snieder, H., Spector, TD., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., van der Harst, P., Völzke, H., Walker, M., Wareham, NJ., Watkins, H., Wichmann, HE., Wilson, JF., Zanen, P., Deloukas, P., Heid, IM., Lindgren, CM., Mohlke, KL., Speliotes, EK., Thorsteinsdottir, U., Barroso£££Inês£££ I., Fox, CS., North, KE., Strachan, DP., Beckmann, JS., Berndt, SI., Boehnke, M., Borecki, IB., McCarthy, MI., Metspalu, A., Stefansson, K., Uitterlinden, AG., van Duijn CM., Franke, L., Willer, CJ., Price, AL., Lettre, G., Loos, RJ., Weedon, MN., Ingelsson, E., O'Connell, JR., Abecasis, GR., Chasman, DI., Goddard, ME., Visscher, PM., Hirschhorn, JN., Frayling, TM., Clinicum, Jaakko Kaprio / Principal Investigator, Department of Public Health, Institute for Molecular Medicine Finland, Genetic Epidemiology, Pers, T, Karjalainen, J, Chan, Y, Westra, H, Wood, A, Yang, J, Lui, J, Vedantam, S, Gustafsson, S, Esko, T, Frayling, T, Speliotes, E, Boehnke, M, Raychaudhuri, S, Fehrmann, R, Hirschhorn, J, Franke, L, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Ferreira, T, Jackson, A, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Winkler, T, Workalemahu, T, Zhao, J, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Fraser, R, Goel, A, Gong, J, Justice, E, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, M, Nyholt, D, Palmer, C, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, J, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Bolton, J, Böttcher, Y, Boyd, H, Bruinenberg, M, Buckley, B, Buyske, S, Caspersen, I, Chines, P, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, E, De Jong, A, Deelen, J, Delgado, G, Denny, J, Dhonukshe Rutten, R, Dimitriou, M, Doney, A, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, M, Geller, F, Giedraitis, V, Go, A, Grallert, H, Grammer, T, Gräßler, J, Grönberg, H, de Groot, L, Groves, C, Haessler, J, Haller, T, Hallmans, G, Hannemann, A, Hartman, C, Hassinen, M, Hayward, C, Heard Costa, N, Helmer, Q, Hemani, G, Henders, A, Hillege, H, Hlatky, M, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat, J, Illig, T, Isaacs, A, James, A, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, A, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, P, Mahajan, A, Maillard, M, Mcardle, W, Mckenzie, C, Mclachlan, S, Mclaren, P, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, K, Morken, M, Müller, G, Müller Nurasyid, M, Musk, A, Narisu, N, Nauck, M, Nolte, I, Nöthen, M, Oozageer, L, Pilz, S, Rayner, N, Renstrom, F, Robertson, N, Rose, L, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Schunkert, H, Scott, R, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, J, Smith, A, Smolonska, J, Stanton, A, Stirrups, K, Stott, D, Stringham, H, Sundström, J, Swertz, M, Syvänen, A, Tayo, B, Thorleifsson, G, Tyrer, J, van Dijk, S, van Schoor, N, van der Velde, N, van Heemst, D, van Oort, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Waldenberger, M, Wennauer, R, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Bergmann, S, Biffar, R, Blangero, J, Boomsma, I, Bornstein, S, Bovet, P, Brambilla, P, Brown, M, Campbell, H, Caulfield, M, Chakravarti, A, Collins, R, Collins, F, Crawford, D, Cupples, L, Danesh, J, de Faire, U, den Ruijter, H, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Ford, I, Forouhi, N, Forrester, T, Gansevoort, R, Gejman, P, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, D, Hall, A, Harris, T, Hattersley, A, Heath, A, Hengstenberg, C, Hicks, A, Hindorff, L, Hingorani, A, Hofman, A, Hovingh, G, Humphries, S, Hunt, S, Hypponen, E, Jacobs, K, Jarvelin, M, Jousilahti, P, Jula, A, Kaprio, J, Kastelein, J, Kayser, M, Kee, F, Keinanen Kiukaanniemi, S, Kiemeney, L, Kooner, J, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, A, Kumari, M, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, P, Männistö, S, Manunta, P, Marette, A, Matise, T, Mcknight, B, Meitinger, T, Moll, F, Montgomery, G, Morris, A, Murray, J, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Ouwehand, W, Pasterkamp, G, Peters, A, Pramstaller, P, Price, J, Qi, L, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Sebert, S, Sever, P, Shuldiner, A, Sinisalo, J, Steinthorsdottir, V, Stolk, R, Tardif, J, Tönjes, A, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, M, Amouyel, P, Asselbergs, F, Assimes, T, Bochud, M, Boehm, B, Boerwinkle, E, Bottinger, E, Bouchard, C, Cauchi, S, Chambers, J, Chanock, S, Cooper, R, de Bakker, P, Dedoussis, G, Ferrucci, L, Franks, P, Froguel, P, Groop, L, Haiman, C, Hamsten, A, Hayes, M, Hui, J, Hunter, D, Hveem, K, Jukema, J, Kaplan, R, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, N, März, W, Melbye, M, Moebus, S, Munroe, P, Njølstad, I, Oostra, B, Pedersen, N, Perola, M, Pérusse, L, Peters, U, Powell, J, Power, C, Quertermous, T, Rauramaa, R, Reinmaa, E, Ridker, P, Rivadeneira, F, Rotter, J, Saaristo, T, Saleheen, D, Schlessinger, D, Slagboom, P, Snieder, H, Spector, T, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Zanen, P, Deloukas, P, Heid, I, Lindgren, C, Mohlke, K, Thorsteinsdottir, U, Barroso, I, Fox, C, North, K, Strachan, D, Beckmann, J, Berndt, S, Borecki, I, Mccarthy, M, Metspalu, A, Stefansson, K, Uitterlinden, A, van Duijn, C, Willer, C, Price, A, Lettre, G, Loos, R, Weedon, M, Ingelsson, E, O'Connell, J, Abecasis, G, Chasman, D, Goddard, M, Visscher, P, APH - Amsterdam Public Health, AMS - Amsterdam Movement Sciences, Geriatrics, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Pers, Th, Karjalainen, Jm, Westra, Hj, Wood, Ar, Lui, Jc, Speliotes, Ek, Hirschhorn, Jn, and Faculty of Health Sciences
Subjects: Cell type, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, LOCI, General Physics and Astronomy, Genome-wide association study, Disease, Computational biology, Biology, Research Support, General Biochemistry, Genetics and Molecular Biology, Article, DISEASE, N.I.H, CANDIDATE GENES, Genome-Wide Association Study/methods, Software, HEIGHT, Research Support, N.I.H., Extramural, Genetics, Journal Article, NETWORK, Non-U.S. Gov't, Gene, COMMON, Intramural, ARCHITECTURE, Biochemistry, Genetics and Molecular Biology (all), Multidisciplinary, IDENTIFICATION, ta1184, Research Support, Non-U.S. Gov't, Gene sets, Extramural, General Chemistry, ta3121, Research Support, N.I.H., Intramural, Phenotype, 3142 Public health care science, environmental and occupational health, Biological sciences, DATA SETS, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Identification (biology), INTEGRATION, Genome-Wide Association Study
Abstract: Article, The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes., published version, http://purl.org/eprint/status/PeerReviewed
Published: 2015

26. Identification of shared risk loci and pathways for bipolar disorder and schizophrenia

Author: Forstner, AJ, Hecker, J, Hofmann, A, Maaser, A, Reinbold, CS, Mühleisen, TW, Leber, M, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Schumacher, J, Streit, F, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Schenk, LM, Fischer, SB, Sivalingam, S, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnov, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Cruceanu, C, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Becker, T, Schulze, TG, Rietschel, M, Cichon, S, Fier, H, Nöthen, MM, Forstner, AJ, Hecker, J, Hofmann, A, Maaser, A, Reinbold, CS, Mühleisen, TW, Leber, M, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Schumacher, J, Streit, F, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Schenk, LM, Fischer, SB, Sivalingam, S, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnov, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Cruceanu, C, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Becker, T, Schulze, TG, Rietschel, M, Cichon, S, Fier, H, and Nöthen, MM
Abstract: Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8 ). This provides further evidence that SCZassociated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
Published: 2017

27. Common variants at 2q11.2, 8q21.3, and 11q13.2 are associated with major mood disorders

Author: Xiao, X, Wang, L, Wang, C, Yuan, TF, Zhou, D, Zheng, F, Li, L, Grigoroiu-Serbanescu, M, Ikeda, M, Iwata, N, Takahashi, A, Kamatani, Y, Kubo, M, Preisig, M, Kutalik, Z, Castelao, E, Pistis, G, Amin, N, Van Duijn, CM, Forstner, AJ, Strohmaier, J, Hecker, J, Schulze, TG, Müller-Myhsok, B, Reif, A, Mitchell, PB, Martin, NG, Schofield, PR, Cichon, S, Nöthen, MM, Chang, H, Luo, XJ, Fang, Y, Yao, YG, Zhang, C, Rietschel, M, Li, M, Xiao, X, Wang, L, Wang, C, Yuan, TF, Zhou, D, Zheng, F, Li, L, Grigoroiu-Serbanescu, M, Ikeda, M, Iwata, N, Takahashi, A, Kamatani, Y, Kubo, M, Preisig, M, Kutalik, Z, Castelao, E, Pistis, G, Amin, N, Van Duijn, CM, Forstner, AJ, Strohmaier, J, Hecker, J, Schulze, TG, Müller-Myhsok, B, Reif, A, Mitchell, PB, Martin, NG, Schofield, PR, Cichon, S, Nöthen, MM, Chang, H, Luo, XJ, Fang, Y, Yao, YG, Zhang, C, Rietschel, M, and Li, M
Abstract: Bipolar disorder (BPD) and major depressive disorder (MDD) are primary major mood disorders. Recent studies suggest that they share certain psychopathological features and common risk genes, but unraveling the full genetic architecture underlying the risk of major mood disorders remains an important scientific task. The public genome-wide association study (GWAS) data sets offer the opportunity to examine this topic by utilizing large amounts of combined genetic data, which should ultimately allow a better understanding of the onset and development of these illnesses. Genome-wide meta-analysis was performed by combining two GWAS data sets on BPD and MDD (19,637 cases and 18,083 controls), followed by replication analyses for the loci of interest in independent 12,364 cases and 76,633 controls from additional samples that were not included in the two GWAS data sets. The single-nucleotide polymorphism (SNP) rs10791889 at 11q13.2 was significant in both discovery and replication samples. When combining all samples, this SNP and multiple other SNPs at 2q11.2 (rs717454), 8q21.3 (rs10103191), and 11q13.2 (rs2167457) exhibited genome-wide significant association with major mood disorders. The SNPs in 2q11.2 and 8q21.3 were novel risk SNPs that were not previously reported, and SNPs at 11q13.2 were in high LD with potential BPD risk SNPs implicated in a previous GWAS. The genome-wide significant loci at 2q11.2 and 11q13.2 exhibited strong effects on the mRNA expression of certain nearby genes in cerebellum. In conclusion, we have identified several novel loci associated with major mood disorders, adding further support for shared genetic risk between BPD and MDD. Our study highlights the necessity and importance of mining public data sets to explore risk genes for complex diseases such as mood disorders.
Published: 2017

28. Hair Cortisol in Twins: Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes.

Author: Rietschel, L, Streit, F, Zhu, G, McAloney, K, Frank, J, Couvy-Duchesne, B, Witt, SH, Binz, TM, CORtisolNETwork (CORNET) Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC), McGrath, J, Hickie, IB, Hansell, NK, Wright, MJ, Gillespie, NA, Forstner, AJ, Schulze, TG, Wüst, S, Nöthen, MM, Baumgartner, MR, Walker, BR, Crawford, AA, Colodro-Conde, L, Medland, SE, Martin, NG, Rietschel, M, Rietschel, L, Streit, F, Zhu, G, McAloney, K, Frank, J, Couvy-Duchesne, B, Witt, SH, Binz, TM, CORtisolNETwork (CORNET) Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC), McGrath, J, Hickie, IB, Hansell, NK, Wright, MJ, Gillespie, NA, Forstner, AJ, Schulze, TG, Wüst, S, Nöthen, MM, Baumgartner, MR, Walker, BR, Crawford, AA, Colodro-Conde, L, Medland, SE, Martin, NG, and Rietschel, M
Abstract: Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
Published: 2017

29. Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2

Author: O'Donovan, MC, Norton, N, Williams, H, Peirce, T, Moskvina, V, Nikolov, I, Hamshere, M, Carroll, L, Georgieva, L, Dwyer, S, Holmans, P, Marchini, JL, Spencer, CCA, Howie, B, Leung, H-T, Giegling, I, Hartmann, AM, Möller, H-J, Morris, DW, Shi, Y, Feng, G, Hoffmann, P, Propping, P, Vasilescu, C, Maier, W, Rietschel, M, Zammit, S, Schumacher, J, Quinn, EM, Schulze, TG, Iwata, N, Ikeda, M, Darvasi, A, Shifman, S, He, L, Duan, J, Sanders, AR, Levinson, DF, Adolfsson, R, Ösby, U, Terenius, L, Jönsson, EG, Cichon, S, Nöthen, MM, Gill, M, Corvin, AP, Rujescu, D, Gejman, PV, Kirov, G, Craddock, N, Williams, NM, Owen, MJ, Buccola, NG, Mowry, BJ, Freedman, R, Amin, F, Black, DW, Silverman, JM, Byerley, WJ, and Cloninger, CR
Subjects: Adult, Male, Linkage disequilibrium, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Cellular and Molecular Neuroscience, Young Adult, Gene Frequency, Meta-Analysis as Topic, Polymorphism (computer science), SNP, Humans, Genetic Predisposition to Disease, Allele, Receptor, Fibroblast Growth Factor, Type 2, Molecular Biology, Allele frequency, Aged, Genetics, Aged, 80 and over, Fibroblast growth factor receptor 2, Chromosomes, Human, Pair 10, Middle Aged, Psychiatry and Mental health, Schizophrenia, Female, Genome-Wide Association Study
Abstract: We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P
Published: 2016

30. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author: Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)
Subjects: Male, Cancer Research, Candidate gene, Epidemiology, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, GENETICS & HEREDITY, Genetics (clinical), Genetics, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Middle Aged, 3. Good health, CYP17A1, Genetic Epidemiology, Genome-wide association, Myocardial-infarction, Susceptibility loci, Risk, Atherosclerosis, Metanalysis, Lipoprotein, Medicine, Female, Life Sciences & Biomedicine, Research Article, Asian Continental Ancestry Group, Adult, SUSCEPTIBILITY LOCI, lcsh:QH426-470, European Continental Ancestry Group, Biology, Polymorphism, Single Nucleotide, coronary artery disease, genetics, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, Genetic variation, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Molecular Biology, Gene, METAANALYSIS, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Cardiovascular Disease Epidemiology, Alleles, 030304 developmental biology, Aged, 0604 Genetics, Science & Technology, Case-control study, Genetic Variation, Human Genetics, Odds ratio, large-scale gene analysis, lcsh:Genetics, LIPOPROTEIN, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Case-Control Studies, Genetics of Disease, IBC 50K CAD Consortium, Developmental Biology, Genome-Wide Association Study
Abstract: Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.
Published: 2016

31. Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Author: Schwantes-An, TH, Zhang, J, Chen, LS, Hartz, SM, Culverhouse, RC, Chen, X, Coon, H, Frank, J, Kamens, HM, Konte, B, Kovanen, L, Latvala, A, Legrand, LN, Maher, BS, Melroy, WE, Nelson, EC, Reid, MW, Robinson, JD, Shen, PH, Yang, BZ, Andrews, JA, Aveyard, P, Beltcheva, O, Brown, SA, Cannon, DS, Cichon, S, Corley, RP, Dahmen, N, Degenhardt, L, Foroud, T, Gaebel, W, Giegling, I, Glatt, SJ, Grucza, RA, Hardin, J, Hartmann, AM, Heath, AC, Herms, S, Hodgkinson, CA, Hoffmann, P, Hops, H, Huizinga, D, Ising, M, Johnson, EO, Johnstone, E, Kaneva, RP, Kendler, KS, Kiefer, F, Kranzler, HR, Krauter, KS, Levran, O, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Martin, NG, Mattheisen, M, Montgomery, GW, Müller-Myhsok, B, Murphy, MF, Neale, MC, Nikolov, MA, Nishita, D, Nöthen, MM, Nurnberger, J, Partonen, T, Pergadia, ML, Reynolds, M, Ridinger, M, Rose, RJ, Rouvinen-Lagerström, N, Scherbaum, N, Schmäl, C, Soyka, M, Stallings, MC, Steffens, M, Treutlein, J, Tsuang, M, Wall, TL, Wodarz, N, Yuferov, V, Zill, P, Bergen, AW, and Chen, J
Abstract: © 2015, Springer Science+Business Media New York. The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for “general” substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95 % C.I. [0.83–0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.
Published: 2016

32. Erste Genotyp – Phänotyp Analyse bei Achalasiepatienten zur Korrelation der HLA-DQB1-Inseration mit den 3 Subtypen der Chicaogo-Klassifikation

Author: Vackova, Z, additional, Niebisch, S, additional, Triantafilou, T, additional, Becker, J, additional, Kosiol, K, additional, Thieme, R, additional, Kreuser, N, additional, Schüller, V, additional, Heinrichs, S, additional, Hess, T, additional, Nöthen, MM, additional, Knapp, M, additional, Spicak, J, additional, Gockel, I, additional, Scheuermann, J, additional, Theodorou, D, additional, and Martinek, J, additional
Published: 2017
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33. Umfangreiche epidemiologische und Genotyp-Phänotyp (GxP) Analysen in dem weltweit größten Patientenkollektiv mit idiopathischer Achalasie

Author: Becker, J, additional, Niebisch, S, additional, Thieme, R, additional, Ricchiuto, A, additional, Schaich, EJ, additional, Lehmann, G, additional, Tobias, W, additional, Schafft, A, additional, Hess, T, additional, Lenze, F, additional, Venerito, M, additional, Hüneburg, R, additional, Lingohr, P, additional, Matthaei, H, additional, Seewald, S, additional, Scheuermann, U, additional, Kreuser, N, additional, Veits, L, additional, Wouters, MM, additional, Gockel, HR, additional, Lang, H, additional, Vieth, M, additional, Müller, M, additional, Eckardt, AJ, additional, Rahden, BHA, additional, Knapp, M, additional, Boeckxstaens, GE, additional, Fimmers, R, additional, Malecka-Panas, E, additional, Marek, T, additional, Dąbrowski, A, additional, Annese, V, additional, Nilsson, M, additional, Urcelay, E, additional, Latiano, A, additional, Fumagalli, U, additional, Rosati, R, additional, Laghi, L, additional, Cuomo, R, additional, Nöthen, MM, additional, Schumacher, J, additional, and Gockel, I, additional
Published: 2017
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34. Evidence for PTGER4, PSCA and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Author: Hess, T, additional, Hamann, L, additional, Vashist, YK, additional, Butterbach, K, additional, Schmidt, T, additional, Krasniuk, I, additional, Höblinger, A, additional, Lingohr, P, additional, Ludwig, M, additional, Hagel, AF, additional, Schildberg, CW, additional, Veits, L, additional, Gyvyte, U, additional, Gonzalez-Carmona, MA, additional, Heinrichs, SK, additional, Becker, J, additional, Lordick, F, additional, Malfertheiner, P, additional, Möhler, M, additional, Pech, O, additional, Rodermann, E, additional, Izbicki, JR, additional, Kruschewski, M, additional, Ott, K, additional, Schumann, RR, additional, Vieth, M, additional, Mangold, E, additional, Kupcinskas, L, additional, Brenner, H, additional, Grimminger, P, additional, Bruns, C, additional, Büchler, MW, additional, Gockel, I, additional, Nöthen, MM, additional, Lippert, H, additional, Ridwelski, K, additional, Lanas, A, additional, Keller, G, additional, Knapp, M, additional, Leja, M, additional, Schumacher, J, additional, Kupcinskas, J, additional, García-González, MA, additional, and Venerito, M, additional
Published: 2017
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35. Genome-wide association study identifies multiple susceptibility loci for glioma

Author: Kinnersley, B, Labussière, M, Holroyd, A, Di Stefano, A-L, Broderick, P, Vijayakrishnan, J, Mokhtari, K, Delattre, J-Y, Gousias, K, Schramm, J, Schoemaker, MJ, Fleming, SJ, Herms, S, Heilmann, S, Schreiber, S, Wichmann, H-E, Nöthen, MM, Swerdlow, A, Lathrop, M, Simon, M, Bondy, M, Sanson, M, and Houlston, RS
Abstract: Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10−9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10−8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10−11), 12q21.2 (rs12230172, P=7.53 × 10−11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10−9). Our findings provide further insights into the genetic basis of the different glioma subtypes.
Published: 2015

36. No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

Author: Johnson, EC, Bjelland, DW, Howrigan, DP, Abdellaoui, A, Breen, G, Borglum, A, Cichon, S, Degenhardt, F, Forstner, AJ, Frank, J, Genovese, G, Heilmann-Heimbach, S, Herms, S, Hoffman, P, Maier, W, Mattheisen, M, Morris, D, Mowry, B, Müller-Mhysok, B, Neale, B, Nenadic, I, Nöthen, MM, O Dushlaine, C, Rietschel, M, Ruderfer, DM, Rujescu, D, Schulze, TG, Simonson, MA, Stahl, E, Strohmaier, J, Witt, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Johnson, EC, Bjelland, DW, Howrigan, DP, Abdellaoui, A, Breen, G, Borglum, A, Cichon, S, Degenhardt, F, Forstner, AJ, Frank, J, Genovese, G, Heilmann-Heimbach, S, Herms, S, Hoffman, P, Maier, W, Mattheisen, M, Morris, D, Mowry, B, Müller-Mhysok, B, Neale, B, Nenadic, I, Nöthen, MM, O Dushlaine, C, Rietschel, M, Ruderfer, DM, Rujescu, D, Schulze, TG, Simonson, MA, Stahl, E, Strohmaier, J, Witt, SH, Ripke, S, Neale, BM, Corvin, A, Walters, JTR, Farh, KH, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, and Cai, G
Abstract: © 2016 Johnson et al. It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest.
Published: 2016

37. Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

Author: Li, M, Huang, L, Grigoroiu-Serbanescu, M, Bergen, SE, Landén, M, Hultman, CM, Forstner, AJ, Strohmaier, J, Hecker, J, Schulze, TG, Müller-Myhsok, B, Reif, A, Mitchell, PB, Martin, NG, Cichon, S, Nöthen, MM, Alkelai, A, Lerer, B, Jamain, S, Leboyer, M, Bellivier, F, Etain, B, Kahn, JP, Henry, C, Rietschel, M, MooDS Consortium, The Swedish Bipolar Study Group, Li, M, Huang, L, Grigoroiu-Serbanescu, M, Bergen, SE, Landén, M, Hultman, CM, Forstner, AJ, Strohmaier, J, Hecker, J, Schulze, TG, Müller-Myhsok, B, Reif, A, Mitchell, PB, Martin, NG, Cichon, S, Nöthen, MM, Alkelai, A, Lerer, B, Jamain, S, Leboyer, M, Bellivier, F, Etain, B, Kahn, JP, Henry, C, Rietschel, M, MooDS Consortium, and The Swedish Bipolar Study Group
Abstract: Reelin (RELN) is identified as a risk gene for major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 (LRP8) in these illnesses is still unclear. To detect whether LRP8 is a susceptibility gene for SCZ and BPD, we analyzed the associations of single nucleotide polymorphisms (SNPs) in LRP8 in a total of 47,187 subjects (including 9379 SCZ patients; 6990 BPD patients; and 12,556 controls in a screening sample, and 1397 SCZ families, 3947 BPD patients, and 8387 controls in independent replications), and identified a non-synonymous SNP rs5174 in LRP8 significantly associated with SCZ and BPD as well as the combined psychosis phenotype (Pmeta = 1.99 × 10−5, odds ratio (OR) = 1.066, 95 % confidence interval (CI) = 1.035–1.098). The risk SNP rs5174 was also associated with LRP8 messenger RNA (mRNA) expression in multiple brain tissues across independent samples (lowest P = 0.00005). Further exploratory analysis revealed that LRP8 was preferentially expressed in fetal brain tissues. Protein-protein interaction (PPI) analysis demonstrated that LRP8 significantly participated in a highly interconnected PPI network build by top risk genes for SCZ and BPD (P = 7.0 × 10−4). Collectively, we confirmed that LRP8 is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involving LRP8 underlying risk of complex psychiatric disorders.
Published: 2016

38. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study

Author: Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, Macqueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, Depaulo, JR, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, Macqueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, and Depaulo, JR
Abstract: Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Hea
Published: 2016

39. Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Author: Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, Ösby, U, Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, and Ösby, U
Abstract: Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Published: 2016

40. Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance

Author: Li, M, Luo, XJ, Landén, M, Bergen, SE, Hultman, CM, Li, X, Zhang, W, Yao, YG, Zhang, C, Liu, J, Mattheisen, M, Cichon, S, Mühleisen, TW, Degenhardt, FA, Nöthen, MM, Schulze, TG, Grigoroiu-Serbanescu, M, Li, H, Fuller, CK, Chen, C, Dong, Q, Jamain, S, Leboyer, M, Bellivier, F, Etain, B, Kahn, JP, Henry, C, Preisig, M, Kutalik, Z, Castelao, E, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Rietschel, M, Liu, C, Kleinman, JE, Hyde, TM, Weinberger, DR, Su, B, Li, M, Luo, XJ, Landén, M, Bergen, SE, Hultman, CM, Li, X, Zhang, W, Yao, YG, Zhang, C, Liu, J, Mattheisen, M, Cichon, S, Mühleisen, TW, Degenhardt, FA, Nöthen, MM, Schulze, TG, Grigoroiu-Serbanescu, M, Li, H, Fuller, CK, Chen, C, Dong, Q, Jamain, S, Leboyer, M, Bellivier, F, Etain, B, Kahn, JP, Henry, C, Preisig, M, Kutalik, Z, Castelao, E, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Rietschel, M, Liu, C, Kleinman, JE, Hyde, TM, Weinberger, DR, and Su, B
Abstract: Background Bipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain. Aims We sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL. Method To detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals. Results Integrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.8561075). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.5461078). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals. Conclusions Our findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.
Published: 2016

41. Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Author: Luo, XJ, Li, M, Huang, L, Steinberg, S, Mattheisen, M, Liang, G, Donohoe, G, Shi, Y, Chen, C, Yue, W, Alkelai, A, Lerer, B, Li, Z, Yi, Q, Rietschel, M, Cichon, S, Collier, DA, Tosato, S, Suvisaari, J, Rujescu, D, Golimbet, V, Silagadze, T, Durmishi, N, Milovancevic, MP, Stefansson, H, Schulze, TG, Nöthen, MM, Lyne, R, Morris, DW, Gill, M, Corvin, A, Zhang, D, Dong, Q, Moyzis, RK, Stefansson, K, Sigurdsson, E, Hu, F, SCZ Consortium36, Su, B, Gan, L, and College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China [2] Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA. 2Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. 31] Nanchang University, Nanchang, China [2] Gannan Medical University, Ganzhou, China [3] Jiangxi Provincial People's Hospital, Nanchang, China. 4deCODE Genetics, Reykjavik, Iceland. 5Department of Biomedicine, Aarhus University, Aarhus C, Denmark. 6College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China. 7Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland. 8Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. 9Department of Psychology and Social Behavior, University of California, Irvine, CA, USA. 101] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China. 11Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 12Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, China. 13Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany. 14Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany. 151] Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK [2] Eli Lilly and Co. Ltd, Erl Wood Manor, Surrey, UK. 16Section of Psychiatry, University of Verona, Verona, Italy. 17Mental Health and Substance Abuse Services, National Institute for Health and Welfare THL, Helsinki, Finland. 181] Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany. 19Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia. 20Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia. 21Department of Child and Adolescent Psychiatry, University of Skopje, Skopje, Macedonia. 22Medical Faculty, University of Belgrade, Belgrade, Serbia. 23Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Goettingen, Germany. 24State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China. 25Department of Biological Chemistry, University of California, Irvine, CA, USA. 261] deCODE Genetics, Reykjavik, Iceland [2] School of Medicine, University of Iceland, Reykjavik, Iceland. 271] School of Medicine, University of Iceland, Reykjavik, Iceland [2] Department of Psychiatry, National University Hospital, Reykjavik, Iceland. 28Affiliated Eye Hospital of Nanchang University, Nanchang, China. 29State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Subjects: Pathogenesis, protein-protein interaction, 0302 clinical medicine, Cognition, Gene expression, Genamengi, Databases, Genetic, Protein Interaction Maps, European Continental Ancestry Group/genetics, Psychotic Disorders/genetics, CAMKK2, Schizophrenic Psychology, Genetics, 0303 health sciences, Brain, Chromosome Mapping, Polymorphism, Single Nucleotide/genetics, Psychiatry and Mental health, Geðsjúkdómar, Personality, Genotype, Schizophrenia (object-oriented programming), Down-Regulation, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Single-nucleotide polymorphism, Calcium-Calmodulin-Dependent Protein Kinase, Biology, eQTL, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Cellular and Molecular Neuroscience, Asian People, Geðklofi, Personality/genetics, Kinase/metabolism, expression, SNP, Brain/metabolism, Humans, Genetic Predisposition to Disease, Asian Continental Ancestry Group/genetics, Allele, Molecular Biology, Gene, association, schizophrenia, Alleles, 030304 developmental biology, Arfgengi, Kinase/genetics, Schizophrenia/genetics, Case-Control Studies, Protein Interaction Maps/genetics, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility. National Natural Science Foundation of China/81271006/ 81060081 Hangzhou City Health Science Foundation/20120633B01 Jiangxi Provincial Natural Science Foundation/2010GZY0089/20114BAB215006 Natural Science Foundation of China/U1202225/81130022/ 81272302/31000553 863 Program 2012AA02A515 EU/HEALTH-2011-286213 HEALTH-F2-2009-223423 111 Project of the Ministry of Education of China/B07008 Israel Science Foundation info:eu-repo/grantAgreement/EC/FP7/286213
Published: 2014

42. Meta-analysis identifies seven susceptibility loci involved in the atopic March

Author: Marenholz, I, Esparza-Gordillo, J, Rüschendorf, F, Bauerfeind, A, Strachan, DP, Spycher, BD, Baurecht, H, Margaritte-Jeannin, P, Sääf, A, Kerkhof, M, Ege, M, Baltic, S, Matheson, MC, Li, J, Michel, S, Ang, WQ, McArdle, W, Arnold, A, Homuth, G, Demenais, F, Bouzigon, E, Söderhäll, C, Pershagen, G, De Jongste, JC, Postma, DS, Braun-Fahrländer, C, Horak, E, Ogorodova, LM, Puzyrev, VP, Bragina, EY, Hudson, TJ, Morin, C, Duffy, DL, Marks, GB, Robertson, CF, Montgomery, GW, Musk, B, Thompson, PJ, Martin, NG, James, A, Sleiman, P, Toskala, E, Rodriguez, E, Fölster-Holst, R, Franke, A, Lieb, W, Gieger, C, Heinzmann, A, Rietschel, E, Keil, T, Cichon, S, Nöthen, MM, Pennell, CE, Sly, PD, Schmidt, CO, Matanovic, A, Schneider, V, Heinig, M, Hübner, N, Holt, PG, Lau, S, Kabesch, M, Weidinger, S, Hakonarson, H, Ferreira, MAR, Laprise, C, Freidin, MB, Genuneit, J, Koppelman, GH, Melén, E, Dizier, MH, Henderson, AJ, Lee, YA, Marenholz, I, Esparza-Gordillo, J, Rüschendorf, F, Bauerfeind, A, Strachan, DP, Spycher, BD, Baurecht, H, Margaritte-Jeannin, P, Sääf, A, Kerkhof, M, Ege, M, Baltic, S, Matheson, MC, Li, J, Michel, S, Ang, WQ, McArdle, W, Arnold, A, Homuth, G, Demenais, F, Bouzigon, E, Söderhäll, C, Pershagen, G, De Jongste, JC, Postma, DS, Braun-Fahrländer, C, Horak, E, Ogorodova, LM, Puzyrev, VP, Bragina, EY, Hudson, TJ, Morin, C, Duffy, DL, Marks, GB, Robertson, CF, Montgomery, GW, Musk, B, Thompson, PJ, Martin, NG, James, A, Sleiman, P, Toskala, E, Rodriguez, E, Fölster-Holst, R, Franke, A, Lieb, W, Gieger, C, Heinzmann, A, Rietschel, E, Keil, T, Cichon, S, Nöthen, MM, Pennell, CE, Sly, PD, Schmidt, CO, Matanovic, A, Schneider, V, Heinig, M, Hübner, N, Holt, PG, Lau, S, Kabesch, M, Weidinger, S, Hakonarson, H, Ferreira, MAR, Laprise, C, Freidin, MB, Genuneit, J, Koppelman, GH, Melén, E, Dizier, MH, Henderson, AJ, and Lee, YA
Abstract: Eczema often precedes the development of asthma in a disease course called the a € atopic marcha €. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
Published: 2015

43. Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder

Author: Forstner, AJ, Hofmann, A, Maaser, A, Sumer, S, Khudayberdiev, S, Mühleisen, TW, Leber, M, Schulze, TG, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Schumacher, J, Breuer, R, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Priebe, L, Sivalingam, S, Verhaert, A, Schulz, H, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnov, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Cruceanu, C, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Propping, P, Becker, T, Rietsche, M, Cichon, S, Schratt, G, Nöthen, MM, Forstner, AJ, Hofmann, A, Maaser, A, Sumer, S, Khudayberdiev, S, Mühleisen, TW, Leber, M, Schulze, TG, Strohmaier, J, Degenhardt, F, Treutlein, J, Mattheisen, M, Schumacher, J, Breuer, R, Meier, S, Herms, S, Hoffmann, P, Lacour, A, Witt, SH, Reif, A, Müller-Myhsok, B, Lucae, S, Maier, W, Schwarz, M, Vedder, H, Kammerer-Ciernioch, J, Pfennig, A, Bauer, M, Hautzinger, M, Moebus, S, Priebe, L, Sivalingam, S, Verhaert, A, Schulz, H, Czerski, PM, Hauser, J, Lissowska, J, Szeszenia-Dabrowska, N, Brennan, P, McKay, JD, Wright, A, Mitchell, PB, Fullerton, JM, Schofield, PR, Montgomery, GW, Medland, SE, Gordon, SD, Martin, NG, Krasnov, V, Chuchalin, A, Babadjanova, G, Pantelejeva, G, Abramova, LI, Tiganov, AS, Polonikov, A, Khusnutdinova, E, Alda, M, Cruceanu, C, Rouleau, GA, Turecki, G, Laprise, C, Rivas, F, Mayoral, F, Kogevinas, M, Grigoroiu-Serbanescu, M, Propping, P, Becker, T, Rietsche, M, Cichon, S, Schratt, G, and Nöthen, MM
Abstract: Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BDassociated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.
Published: 2015

44. Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Author: FTO-Mortality Collaborating Group, Orho-Melander, M., Zillikens, C., Ikram, A., Hofman, A., Luan, J., Khaw, KT., Rose, LM., Läll, K., Mägi, R., Qi, L., Sun, Q., Harris, TB., Launer, LJ., Eiriksdottir, G., Kleber, ME., Delgado, G., Liu, Y., Garcia, M., Teumer, A., Grabe, H., Homuth, G., Jukema, JW., Ford, I., de Craen AJ., Gallacher, J., Yarnell, J., Mahabadi, AA., Nöthen, MM., Erbel, R., Stringham, HM., Boehnke, M., Amouyel, P., Ferrières, J., Arveiler, D., Kähönen, M., Nikus, K., Nieminen, T., Sanchez, A., Kivimaki, M., van Vliet-Ostaptchouk JV., Hampel, R., Thorand, B., De Faire, U., Nyberg, F., Kuh, D., Martin, NG., Montgomery, GW., Heath, AC., Madden, PA., Osmond, C., Pulizzi, N., Roswall, N., Halkjaer, J., Overvad, K., Uusitupa, M., Kinnunen, L., Lindström, J., Saramies, J., Keinänen-Kiukaanniemi, S., Uusitalo, H., Hussi, E., Baldassarre, D., Veglia, F., Humphries, S., Tremoli, E., Heitmann, B., Zimmermann, E., Ängquist, L.H., Mirza, S.S., Zhao, J.H., Chasman, D.I., Fischer, K., Qi, Q., Smith, A.V., Thinggaard, M., Jarczok, M.N., Nalls, M.A., Trompet, S., Timpson, N.J., Schmidt, B., Jackson, A.U., Lyytikäinen, L.P., Verweij, N., Mueller-Nurasyid, M., Vikström, M., Marques-Vidal, P., Wong, A., Meidtner, K., Middelberg, R.P., Strawbridge, R.J., Christiansen, L., Kyvik, K.O., Hamsten, A., Jääskeläinen, T., Tjønneland, A., Eriksson, J.G., Whitfield, J.B., Boeing, H., Hardy, R., Vollenweider, P., Leander, K., Peters, A., van der Harst, P., Kumari, M., Lehtimäki, T., Meirhaeghe, A., Tuomilehto, J., Jöckel, K.H., Ben-Shlomo, Y., Sattar, N., Baumeister, S.E., Davey Smith, G., Casas, J.P., Houston, D.K., März, W., Christensen, K., Gudnason, V., Hu, F.B., Metspalu, A., Ridker, P.M., Wareham, N.J., Loos, R.J., Tiemeier, H., Sonestedt, E., Sørensen, T.I., FTO-Mortality Collaborating Group, Orho-Melander, M., Zillikens, C., Ikram, A., Hofman, A., Luan, J., Khaw, KT., Rose, LM., Läll, K., Mägi, R., Qi, L., Sun, Q., Harris, TB., Launer, LJ., Eiriksdottir, G., Kleber, ME., Delgado, G., Liu, Y., Garcia, M., Teumer, A., Grabe, H., Homuth, G., Jukema, JW., Ford, I., de Craen AJ., Gallacher, J., Yarnell, J., Mahabadi, AA., Nöthen, MM., Erbel, R., Stringham, HM., Boehnke, M., Amouyel, P., Ferrières, J., Arveiler, D., Kähönen, M., Nikus, K., Nieminen, T., Sanchez, A., Kivimaki, M., van Vliet-Ostaptchouk JV., Hampel, R., Thorand, B., De Faire, U., Nyberg, F., Kuh, D., Martin, NG., Montgomery, GW., Heath, AC., Madden, PA., Osmond, C., Pulizzi, N., Roswall, N., Halkjaer, J., Overvad, K., Uusitupa, M., Kinnunen, L., Lindström, J., Saramies, J., Keinänen-Kiukaanniemi, S., Uusitalo, H., Hussi, E., Baldassarre, D., Veglia, F., Humphries, S., Tremoli, E., Heitmann, B., Zimmermann, E., Ängquist, L.H., Mirza, S.S., Zhao, J.H., Chasman, D.I., Fischer, K., Qi, Q., Smith, A.V., Thinggaard, M., Jarczok, M.N., Nalls, M.A., Trompet, S., Timpson, N.J., Schmidt, B., Jackson, A.U., Lyytikäinen, L.P., Verweij, N., Mueller-Nurasyid, M., Vikström, M., Marques-Vidal, P., Wong, A., Meidtner, K., Middelberg, R.P., Strawbridge, R.J., Christiansen, L., Kyvik, K.O., Hamsten, A., Jääskeläinen, T., Tjønneland, A., Eriksson, J.G., Whitfield, J.B., Boeing, H., Hardy, R., Vollenweider, P., Leander, K., Peters, A., van der Harst, P., Kumari, M., Lehtimäki, T., Meirhaeghe, A., Tuomilehto, J., Jöckel, K.H., Ben-Shlomo, Y., Sattar, N., Baumeister, S.E., Davey Smith, G., Casas, J.P., Houston, D.K., März, W., Christensen, K., Gudnason, V., Hu, F.B., Metspalu, A., Ridker, P.M., Wareham, N.J., Loos, R.J., Tiemeier, H., Sonestedt, E., and Sørensen, T.I.
Abstract: Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.
Published: 2015

45. Biological interpretation of genome-wide association studies using predicted gene functions

Author: Pers, T, Karjalainen, J, Chan, Y, Westra, H, Wood, A, Yang, J, Lui, J, Vedantam, S, Gustafsson, S, Esko, T, Frayling, T, Speliotes, E, Boehnke, M, Raychaudhuri, S, Fehrmann, R, Hirschhorn, J, Franke, L, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Ferreira, T, Jackson, A, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Winkler, T, Workalemahu, T, Zhao, J, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Fraser, R, Goel, A, Gong, J, Justice, E, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, M, Nyholt, D, Palmer, C, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, J, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Bolton, J, Böttcher, Y, Boyd, H, Bruinenberg, M, Buckley, B, Buyske, S, Caspersen, I, Chines, P, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, E, De Jong, A, Deelen, J, Delgado, G, Denny, J, Dhonukshe Rutten, R, Dimitriou, M, Doney, A, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, M, Geller, F, Giedraitis, V, Go, A, Grallert, H, Grammer, T, Gräßler, J, Grönberg, H, de Groot, L, Groves, C, Haessler, J, Haller, T, Hallmans, G, Hannemann, A, Hartman, C, Hassinen, M, Hayward, C, Heard Costa, N, Helmer, Q, Hemani, G, Henders, A, Hillege, H, Hlatky, M, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat, J, Illig, T, Isaacs, A, James, A, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, A, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, P, Mahajan, A, Maillard, M, Mcardle, W, Mckenzie, C, Mclachlan, S, Mclaren, P, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, K, Morken, M, Müller, G, Müller Nurasyid, M, Musk, A, Narisu, N, Nauck, M, Nolte, I, Nöthen, M, Oozageer, L, Pilz, S, Rayner, N, Renstrom, F, Robertson, N, Rose, L, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Schunkert, H, Scott, R, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, J, Smith, A, Smolonska, J, Stanton, A, Stirrups, K, Stott, D, Stringham, H, Sundström, J, Swertz, M, Syvänen, A, Tayo, B, Thorleifsson, G, Tyrer, J, van Dijk, S, van Schoor, N, van der Velde, N, van Heemst, D, van Oort, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Waldenberger, M, Wennauer, R, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Bergmann, S, Biffar, R, Blangero, J, Boomsma, I, Bornstein, S, Bovet, P, Brambilla, P, Brown, M, Campbell, H, Caulfield, M, Chakravarti, A, Collins, R, Collins, F, Crawford, D, Cupples, L, Danesh, J, de Faire, U, den Ruijter, H, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Ford, I, Forouhi, N, Forrester, T, Gansevoort, R, Gejman, P, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, D, Hall, A, Harris, T, Hattersley, A, Heath, A, Hengstenberg, C, Hicks, A, Hindorff, L, Hingorani, A, Hofman, A, Hovingh, G, Humphries, S, Hunt, S, Hypponen, E, Jacobs, K, Jarvelin, M, Jousilahti, P, Jula, A, Kaprio, J, Kastelein, J, Kayser, M, Kee, F, Keinanen Kiukaanniemi, S, Kiemeney, L, Kooner, J, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, A, Kumari, M, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, P, Männistö, S, Manunta, P, Marette, A, Matise, T, Mcknight, B, Meitinger, T, Moll, F, Montgomery, G, Morris, A, Murray, J, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Ouwehand, W, Pasterkamp, G, Peters, A, Pramstaller, P, Price, J, Qi, L, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Sebert, S, Sever, P, Shuldiner, A, Sinisalo, J, Steinthorsdottir, V, Stolk, R, Tardif, J, Tönjes, A, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, M, Amouyel, P, Asselbergs, F, Assimes, T, Bochud, M, Boehm, B, Boerwinkle, E, Bottinger, E, Bouchard, C, Cauchi, S, Chambers, J, Chanock, S, Cooper, R, de Bakker, P, Dedoussis, G, Ferrucci, L, Franks, P, Froguel, P, Groop, L, Haiman, C, Hamsten, A, Hayes, M, Hui, J, Hunter, D, Hveem, K, Jukema, J, Kaplan, R, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, N, März, W, Melbye, M, Moebus, S, Munroe, P, Njølstad, I, Oostra, B, Pedersen, N, Perola, M, Pérusse, L, Peters, U, Powell, J, Power, C, Quertermous, T, Rauramaa, R, Reinmaa, E, Ridker, P, Rivadeneira, F, Rotter, J, Saaristo, T, Saleheen, D, Schlessinger, D, Slagboom, P, Snieder, H, Spector, T, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Zanen, P, Deloukas, P, Heid, I, Lindgren, C, Mohlke, K, Thorsteinsdottir, U, Barroso, I, Fox, C, North, K, Strachan, D, Beckmann, J, Berndt, S, Borecki, I, Mccarthy, M, Metspalu, A, Stefansson, K, Uitterlinden, A, van Duijn, C, Willer, C, Price, A, Lettre, G, Loos, R, Weedon, M, Ingelsson, E, O'Connell, J, Abecasis, G, Chasman, D, Goddard, M, Visscher, P, Pers TH, Karjalainen JM, Chan Y, Westra HJ, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, Frayling T, Speliotes EK, Boehnke M, Raychaudhuri S, Fehrmann RS, Hirschhorn JN, Franke L, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Mägi R, Mihailov E, Porcu E, Randall JC, Scherag A, Vinkhuyzen AA, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice E, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Mateo Leach I, Medina Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Ärnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Bolton JL, Böttcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Chines PS, Clarke R, Claudi Boehm S, Cooper M, Daw EW, De Jong A, Deelen J, Delgado G, Denny JC, Dhonukshe Rutten R, Dimitriou M, Doney AS, Dörr M, Eklund N, Eury E, Folkersen L, Garcia ME, Geller F, Giedraitis V, Go AS, Grallert H, Grammer TB, Gräßler J, Grönberg H, de Groot LC, Groves CJ, Haessler J, Haller T, Hallmans G, Hannemann A, Hartman CA, Hassinen M, Hayward C, Heard Costa NL, Helmer Q, Hemani G, Henders AK, Hillege HL, Hlatky MA, Hoffmann W, Hoffmann P, Holmen O, Houwing Duistermaat JJ, Illig T, Isaacs A, James AL, Jeff J, Johansen B, Johansson Å, Jolley J, Juliusdottir T, Junttila J, Kho AN, Kinnunen L, Klopp N, Kocher T, Kratzer W, Lichtner P, Lind L, Lindström J, Lobbens S, Lorentzon M, Lu Y, Lyssenko V, Magnusson PK, Mahajan A, Maillard M, McArdle WL, McKenzie CA, McLachlan S, McLaren PJ, Menni C, Merger S, Milani L, Moayyeri A, Monda KL, Morken MA, Müller G, Müller Nurasyid M, Musk AW, Narisu N, Nauck M, Nolte IM, Nöthen MM, Oozageer L, Pilz S, Rayner NW, Renstrom F, Robertson NR, Rose LM, Roussel R, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Schunkert H, Scott RA, Sehmi J, Seufferlein T, Shi J, Silventoinen K, Smit JH, Smith AV, Smolonska J, Stanton AV, Stirrups K, Stott DJ, Stringham HM, Sundström J, Swertz MA, Syvänen AC, Tayo BO, Thorleifsson G, Tyrer JP, van Dijk S, van Schoor NM, van der Velde N, van Heemst D, van Oort FV, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Waldenberger M, Wennauer R, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Arveiler D, Bakker SJ, Beilby J, Bergman RN, Bergmann S, Biffar R, Blangero J, Boomsma I, Bornstein SR, Bovet P, BRAMBILLA, PAOLO, Brown MJ, Campbell H, Caulfield MJ, Chakravarti A, Collins R, Collins FS, Crawford DC, Cupples LA, Danesh J, de Faire U, den Ruijter HM, Erbel R, Erdmann J, Eriksson JG, Farrall M, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Gansevoort RT, Gejman PV, Gieger C, Golay A, Gottesman O, Gudnason V, Gyllensten U, Haas DW, Hall AS, Harris TB, Hattersley AT, Heath AC, Hengstenberg C, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Jacobs KB, Jarvelin MR, Jousilahti P, Jula AM, Kaprio J, Kastelein JJ, Kayser M, Kee F, Keinanen Kiukaanniemi SM, Kiemeney LA, Kooner JS, Kooperberg C, Koskinen S, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lupoli S, Madden PA, Männistö S, Manunta P, Marette A, Matise TC, McKnight B, Meitinger T, Moll FL, Montgomery GW, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Ouwehand WH, Pasterkamp G, Peters A, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ritchie M, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schwarz PE, Sebert S, Sever P, Shuldiner AR, Sinisalo J, Steinthorsdottir V, Stolk RP, Tardif JC, Tönjes A, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PI, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hayes MG, Hui J, Hunter DJ, Hveem K, Jukema JW, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Powell JE, Power C, Quertermous T, Rauramaa R, Reinmaa E, Ridker PM, Rivadeneira F, Rotter JI, Saaristo TE, Saleheen D, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Strauch K, Stumvoll M, Tuomilehto J, Uusitupa M, van der Harst P, Völzke H, Walker M, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Zanen P, Deloukas P, Heid IM, Lindgren CM, Mohlke KL, Thorsteinsdottir U, Barroso I, Fox CS, North KE, Strachan DP, Beckmann JS, Berndt SI, Borecki IB, McCarthy MI, Metspalu A, Stefansson K, Uitterlinden AG, van Duijn CM, Willer CJ, Price AL, Lettre G, Loos RJ, Weedon MN, Ingelsson E, O'Connell JR, Abecasis GR, Chasman DI, Goddard ME, Visscher PM, Frayling T.M., Pers, T, Karjalainen, J, Chan, Y, Westra, H, Wood, A, Yang, J, Lui, J, Vedantam, S, Gustafsson, S, Esko, T, Frayling, T, Speliotes, E, Boehnke, M, Raychaudhuri, S, Fehrmann, R, Hirschhorn, J, Franke, L, Chu, A, Estrada, K, Luan, J, Kutalik, Z, Amin, N, Buchkovich, M, Croteau Chonka, D, Day, F, Duan, Y, Fall, T, Ferreira, T, Jackson, A, Lo, K, Locke, A, Mägi, R, Mihailov, E, Porcu, E, Randall, J, Scherag, A, Vinkhuyzen, A, Winkler, T, Workalemahu, T, Zhao, J, Absher, D, Albrecht, E, Anderson, D, Baron, J, Beekman, M, Demirkan, A, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Fraser, R, Goel, A, Gong, J, Justice, E, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Mateo Leach, I, Medina Gomez, C, Nalls, M, Nyholt, D, Palmer, C, Pasko, D, Pechlivanis, S, Prokopenko, I, Ried, J, Ripke, S, Shungin, D, Stancáková, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Afzal, U, Ärnlöv, J, Arscott, G, Bandinelli, S, Barrett, A, Bellis, C, Bennett, A, Berne, C, Blüher, M, Bolton, J, Böttcher, Y, Boyd, H, Bruinenberg, M, Buckley, B, Buyske, S, Caspersen, I, Chines, P, Clarke, R, Claudi Boehm, S, Cooper, M, Daw, E, De Jong, A, Deelen, J, Delgado, G, Denny, J, Dhonukshe Rutten, R, Dimitriou, M, Doney, A, Dörr, M, Eklund, N, Eury, E, Folkersen, L, Garcia, M, Geller, F, Giedraitis, V, Go, A, Grallert, H, Grammer, T, Gräßler, J, Grönberg, H, de Groot, L, Groves, C, Haessler, J, Haller, T, Hallmans, G, Hannemann, A, Hartman, C, Hassinen, M, Hayward, C, Heard Costa, N, Helmer, Q, Hemani, G, Henders, A, Hillege, H, Hlatky, M, Hoffmann, W, Hoffmann, P, Holmen, O, Houwing Duistermaat, J, Illig, T, Isaacs, A, James, A, Jeff, J, Johansen, B, Johansson, Å, Jolley, J, Juliusdottir, T, Junttila, J, Kho, A, Kinnunen, L, Klopp, N, Kocher, T, Kratzer, W, Lichtner, P, Lind, L, Lindström, J, Lobbens, S, Lorentzon, M, Lu, Y, Lyssenko, V, Magnusson, P, Mahajan, A, Maillard, M, Mcardle, W, Mckenzie, C, Mclachlan, S, Mclaren, P, Menni, C, Merger, S, Milani, L, Moayyeri, A, Monda, K, Morken, M, Müller, G, Müller Nurasyid, M, Musk, A, Narisu, N, Nauck, M, Nolte, I, Nöthen, M, Oozageer, L, Pilz, S, Rayner, N, Renstrom, F, Robertson, N, Rose, L, Roussel, R, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Schunkert, H, Scott, R, Sehmi, J, Seufferlein, T, Shi, J, Silventoinen, K, Smit, J, Smith, A, Smolonska, J, Stanton, A, Stirrups, K, Stott, D, Stringham, H, Sundström, J, Swertz, M, Syvänen, A, Tayo, B, Thorleifsson, G, Tyrer, J, van Dijk, S, van Schoor, N, van der Velde, N, van Heemst, D, van Oort, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Waldenberger, M, Wennauer, R, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Bergmann, S, Biffar, R, Blangero, J, Boomsma, I, Bornstein, S, Bovet, P, Brambilla, P, Brown, M, Campbell, H, Caulfield, M, Chakravarti, A, Collins, R, Collins, F, Crawford, D, Cupples, L, Danesh, J, de Faire, U, den Ruijter, H, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Ferrannini, E, Ferrières, J, Ford, I, Forouhi, N, Forrester, T, Gansevoort, R, Gejman, P, Gieger, C, Golay, A, Gottesman, O, Gudnason, V, Gyllensten, U, Haas, D, Hall, A, Harris, T, Hattersley, A, Heath, A, Hengstenberg, C, Hicks, A, Hindorff, L, Hingorani, A, Hofman, A, Hovingh, G, Humphries, S, Hunt, S, Hypponen, E, Jacobs, K, Jarvelin, M, Jousilahti, P, Jula, A, Kaprio, J, Kastelein, J, Kayser, M, Kee, F, Keinanen Kiukaanniemi, S, Kiemeney, L, Kooner, J, Kooperberg, C, Koskinen, S, Kovacs, P, Kraja, A, Kumari, M, Kuusisto, J, Lakka, T, Langenberg, C, Le Marchand, L, Lehtimäki, T, Lupoli, S, Madden, P, Männistö, S, Manunta, P, Marette, A, Matise, T, Mcknight, B, Meitinger, T, Moll, F, Montgomery, G, Morris, A, Murray, J, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Ouwehand, W, Pasterkamp, G, Peters, A, Pramstaller, P, Price, J, Qi, L, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schwarz, P, Sebert, S, Sever, P, Shuldiner, A, Sinisalo, J, Steinthorsdottir, V, Stolk, R, Tardif, J, Tönjes, A, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, M, Amouyel, P, Asselbergs, F, Assimes, T, Bochud, M, Boehm, B, Boerwinkle, E, Bottinger, E, Bouchard, C, Cauchi, S, Chambers, J, Chanock, S, Cooper, R, de Bakker, P, Dedoussis, G, Ferrucci, L, Franks, P, Froguel, P, Groop, L, Haiman, C, Hamsten, A, Hayes, M, Hui, J, Hunter, D, Hveem, K, Jukema, J, Kaplan, R, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, N, März, W, Melbye, M, Moebus, S, Munroe, P, Njølstad, I, Oostra, B, Pedersen, N, Perola, M, Pérusse, L, Peters, U, Powell, J, Power, C, Quertermous, T, Rauramaa, R, Reinmaa, E, Ridker, P, Rivadeneira, F, Rotter, J, Saaristo, T, Saleheen, D, Schlessinger, D, Slagboom, P, Snieder, H, Spector, T, Strauch, K, Stumvoll, M, Tuomilehto, J, Uusitupa, M, van der Harst, P, Völzke, H, Walker, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Zanen, P, Deloukas, P, Heid, I, Lindgren, C, Mohlke, K, Thorsteinsdottir, U, Barroso, I, Fox, C, North, K, Strachan, D, Beckmann, J, Berndt, S, Borecki, I, Mccarthy, M, Metspalu, A, Stefansson, K, Uitterlinden, A, van Duijn, C, Willer, C, Price, A, Lettre, G, Loos, R, Weedon, M, Ingelsson, E, O'Connell, J, Abecasis, G, Chasman, D, Goddard, M, Visscher, P, Pers TH, Karjalainen JM, Chan Y, Westra HJ, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T, Frayling T, Speliotes EK, Boehnke M, Raychaudhuri S, Fehrmann RS, Hirschhorn JN, Franke L, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Mägi R, Mihailov E, Porcu E, Randall JC, Scherag A, Vinkhuyzen AA, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice E, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Mateo Leach I, Medina Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Ärnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Bolton JL, Böttcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Chines PS, Clarke R, Claudi Boehm S, Cooper M, Daw EW, De Jong A, Deelen J, Delgado G, Denny JC, Dhonukshe Rutten R, Dimitriou M, Doney AS, Dörr M, Eklund N, Eury E, Folkersen L, Garcia ME, Geller F, Giedraitis V, Go AS, Grallert H, Grammer TB, Gräßler J, Grönberg H, de Groot LC, Groves CJ, Haessler J, Haller T, Hallmans G, Hannemann A, Hartman CA, Hassinen M, Hayward C, Heard Costa NL, Helmer Q, Hemani G, Henders AK, Hillege HL, Hlatky MA, Hoffmann W, Hoffmann P, Holmen O, Houwing Duistermaat JJ, Illig T, Isaacs A, James AL, Jeff J, Johansen B, Johansson Å, Jolley J, Juliusdottir T, Junttila J, Kho AN, Kinnunen L, Klopp N, Kocher T, Kratzer W, Lichtner P, Lind L, Lindström J, Lobbens S, Lorentzon M, Lu Y, Lyssenko V, Magnusson PK, Mahajan A, Maillard M, McArdle WL, McKenzie CA, McLachlan S, McLaren PJ, Menni C, Merger S, Milani L, Moayyeri A, Monda KL, Morken MA, Müller G, Müller Nurasyid M, Musk AW, Narisu N, Nauck M, Nolte IM, Nöthen MM, Oozageer L, Pilz S, Rayner NW, Renstrom F, Robertson NR, Rose LM, Roussel R, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Schunkert H, Scott RA, Sehmi J, Seufferlein T, Shi J, Silventoinen K, Smit JH, Smith AV, Smolonska J, Stanton AV, Stirrups K, Stott DJ, Stringham HM, Sundström J, Swertz MA, Syvänen AC, Tayo BO, Thorleifsson G, Tyrer JP, van Dijk S, van Schoor NM, van der Velde N, van Heemst D, van Oort FV, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Waldenberger M, Wennauer R, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Arveiler D, Bakker SJ, Beilby J, Bergman RN, Bergmann S, Biffar R, Blangero J, Boomsma I, Bornstein SR, Bovet P, BRAMBILLA, PAOLO, Brown MJ, Campbell H, Caulfield MJ, Chakravarti A, Collins R, Collins FS, Crawford DC, Cupples LA, Danesh J, de Faire U, den Ruijter HM, Erbel R, Erdmann J, Eriksson JG, Farrall M, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Gansevoort RT, Gejman PV, Gieger C, Golay A, Gottesman O, Gudnason V, Gyllensten U, Haas DW, Hall AS, Harris TB, Hattersley AT, Heath AC, Hengstenberg C, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Jacobs KB, Jarvelin MR, Jousilahti P, Jula AM, Kaprio J, Kastelein JJ, Kayser M, Kee F, Keinanen Kiukaanniemi SM, Kiemeney LA, Kooner JS, Kooperberg C, Koskinen S, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lupoli S, Madden PA, Männistö S, Manunta P, Marette A, Matise TC, McKnight B, Meitinger T, Moll FL, Montgomery GW, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Ouwehand WH, Pasterkamp G, Peters A, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ritchie M, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schwarz PE, Sebert S, Sever P, Shuldiner AR, Sinisalo J, Steinthorsdottir V, Stolk RP, Tardif JC, Tönjes A, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PI, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hayes MG, Hui J, Hunter DJ, Hveem K, Jukema JW, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Powell JE, Power C, Quertermous T, Rauramaa R, Reinmaa E, Ridker PM, Rivadeneira F, Rotter JI, Saaristo TE, Saleheen D, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Strauch K, Stumvoll M, Tuomilehto J, Uusitupa M, van der Harst P, Völzke H, Walker M, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Zanen P, Deloukas P, Heid IM, Lindgren CM, Mohlke KL, Thorsteinsdottir U, Barroso I, Fox CS, North KE, Strachan DP, Beckmann JS, Berndt SI, Borecki IB, McCarthy MI, Metspalu A, Stefansson K, Uitterlinden AG, van Duijn CM, Willer CJ, Price AL, Lettre G, Loos RJ, Weedon MN, Ingelsson E, O'Connell JR, Abecasis GR, Chasman DI, Goddard ME, Visscher PM, and Frayling T.M.
Abstract: The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.
Published: 2015

46. TREM2 variants in Alzheimer's disease

Author: Guerreiro, R, Wojtas, A, Bras, J, Carrasquillo, M, Rogaeva, E, Majounie, E, Cruchaga, C, Sassi, C, Kauwe, Js, Lupton, Mk, Ryten, M, Brown, K, Lowe, J, Ridge, Pg, Hammer, Mb, Wakutani, Y, Hazrati, L, Proitsi, P, Newhouse, S, Lohmann, E, Erginel Unaltuna, N, Medway, C, Hanagasi, H, Troakes, C, Gurvit, H, Bilgic, B, Al Sarraj, S, Benitez, B, Cooper, B, Carrell, D, Emre, M, Zou, F, Ma, L, Murray, M, Dickson, D, Younkin, S, Petersen, Rc, Corcoran, Cd, Cai, Y, Oliveira, C, Ribeiro, Mh, Santana, I, Tschanz, Jt, Gibbs, J, Norton, Mc, Kloszewska, I, Mecocci, Patrizia, Soininen, H, Tsolaki, M, Vellas, B, Munger, Rg, Mann, Dm, Pickering Brown, S, Lovestone, S, Beck, J, Mead, S, Collinge, J, Parsons, L, Pocock, J, Morris, Jc, Revesz, T, Lashley, T, Fox, Nc, Rossor, Mn, Grenier Boley, B, Bellenguez, C, Moskvina, V, Sims, R, Harold, D, Williams, J, Lambert, Jc, Amouyel, P, Graff Radford, N, Goate, A, Rademakers, R, Morgan, K, Powell, J, St George Hyslop, P, Singleton, A, Hardy, J, Gerrish, A, Chapman, J, Abraham, R, Hollingworth, P, Hamshere, M, Pahwa, Js, Dowzell, K, Williams, A, Jones, N, Thomas, C, Stretton, A, Morgan, A, Williams, K, Thomas, S, Brayne, C, Rubinsztein, Dc, Gill, M, Lawlor, B, Lynch, A, Passmore, P, Craig, D, Mcguinness, B, Johnston, Ja, Todd, S, Holmes, C, Smith, A, Love, S, Kehoe, Pg, Maier, W, Jessen, F, Heun, R, Kölsch, H, Schürmann, B, Ramirez, A, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Hüll, M, Rujescu, D, Nowotny, P, Mayo, K, Livingston, G, Bass, Nj, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Nöthen, Mm, Holmans, P, O'Donovan, M, Owen, Mj, Zelenika, D, Epelbaum, J, Dartigues, Jf, Tzourio, C, Berr, C, Boland, A, Campion, D, Alpérovitch, A, Lathrop, M, Smith, C, Trabzuni, D, Walker, R, Weale, M., Wiltfang, J. (Beitragende*r), EADI Consortium, GERAD Consortium, UKBE Consortium, and Alzheimer Genetic Anal Grp
Subjects: Genetics, TREM2, SORL1, Medizin, Genome-wide association study, General Medicine, Biology, medicine.disease, PSEN2, medicine, Dementia, Human medicine, Alzheimer's disease, Exome, Common disease-common variant
Abstract: BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P
Published: 2013

47. Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

Author: Terwisscha van Scheltinga, Af, Bakker, Sc, van Haren, Ne, Derks, Em, Buizer Voskamp, Je, Boos, Hb, Cahn, W, Hulshoff, Pol, Ripke, S, Ophoff, Ra, Kahn, Rs, Sanders, Ar, Kendler, Ks, Levinson, Df, Sklar, P, Holmans, Pa, Lin, Dy, Duan, J, Andreassen, Oa, Scolnick, E, Cichon, S, Clair, St, D, Corvin, A, Gurling, H, Werge, T, Rujescu, D, Blackwood, Dh, Pato, Cn, Malhotra, Ak, Purcell, S, Dudbridge, F, Neale, Bm, Rossin, L, Visscher, Pm, Posthuma, D, Ruderfer, Dm, Fanous, A, Stefansson, H, Steinberg, S, Mowry, Bj, Golimbet, V, Hert, De, M, Jonsson, Eg, Bitter, I, Pietiläinen, Op, Collier, Da, Tosato, Sarah, Agartz, I, Albus, M, Alexander, M, Amdur, Rl, Amin, F, Bass, N, Bergen, Se, Black, Dw, Børglum, Ad, Brown, Ma, Bruggeman, R, Buccola, Ng, Byerley, Wf, Cantor, Rm, Carr, Vj, Catts, Sv, Choudhury, K, Cloninger, C, Cormican, P, Craddock, N, Danoy, Pa, Datta, S, Haan, De, L, Demontis, D, Dikeos, D, Djurovic, S, Donnelly, P, Donohoe, G, Duong, L, Dwyer, S, Fink Jensen, A, Freedman, R, Freimer, Nb, Friedl, M, Georgieva, L, Giegline, I, Gill, M, Glenthøj, B, Godard, S, Hamshere, M, Hansen, M, Hansen, T, Hartmann, Am, Henskens, Fa, Hougaard, Dm, Hultman, Cm, Ingason, A, Jablensky, Av, Jakobsen, Kd, Jay, M, Jürgens, G, Keller, Mc, Kenis, G, Kenny, E, Kim, Y, Kirov, Gk, Konnerth, H, Konte, B, Krabbendam, L, Krasucki, R, Lasseter, Vk, Laurent, C, Lawrence, J, Lencz, T, Lerer, F, Liang, Ky, Lichtenstein, P, Lieberman, Ja, Linszen, Dh, Lönnqvist, J, Loughland, Cm, Maclean, Aw, Maher, Bs, Maier, W, Mallet, J, Malloy, P, Mattheisen, M, Mattingsdal, M, Mcghee, Ka, Mcgrath, Jj, Mcintosh, A, Mclean, De, Mcquillin, A, Melle, I, Michie, Pt, Milanova, V, Morris, Dw, Mors, O, Mortensen, Pb, Moskvina, V, Muglia, P, Myin Germeys, I, Nertney, Da, Nestadt, G, Nielsen, J, Nikolov, I, Nordentoft, M, Norton, N, Nöthen, Mm, O'Dushlaine, C, Olincy, A, Olsen, L, O'Neill, F, Ørntoft, Tf, Owen, Mj, Pantelis, C, Papadimitriou, G, Pato, Mt, Peltonen, L, Petursson, H, Pickard, B, Pimm, J, Pulver, Ae, Puri, V, Quested, D, Quinn, Em, Rasmussen, Hb, Réthelyi, Jm, Ribble, R, Rietschel, M, Riley, Bp, Ruggeri, Mirella, Schall, U, Schulze, Tg, Schwab, Sg, Scott, Rj, Shi, J, Sigurdsson, E, Silverman, Jm, Spencer, Cc, Stefansson, K, Strange, A, Strengman, E, Stroup, Ts, Suvisaari, J, Terenius, L, Thirumalai, S, Thygesen, Jh, Timm, S, Toncheva, D, van den Oord, E, van Os, J, Van, Winkel, R, Veldink, J, Walsh, D, Wang, Ag, Wiersma, D, Wildenauer, Db, Williams, Hj, Williams, Nm, Wormley, B, Zammit, S, Sullivan, Pf, O'Donovan, Mc, Daly, Mj, Gejman, Pv, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Adult Psychiatry, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Myin-Germeys, Inez, De Hert, Marc, and van Winkel, Ruud
Subjects: Adult, Male, Psychosis, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Biology, Nerve Fibers, Myelinated, Polymorphism, Single Nucleotide, Article, White matter, genome-wide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, mental disorders, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Biological Psychiatry, structural MRI, Genetics, neuroimaging, Case-control study, Brain, imaging, medicine.disease, 030227 psychiatry, 3. Good health, schizophrenia, Endophenotype, Phenotype, medicine.anatomical_structure, psychiatric, Schizophrenia, Case-Control Studies, Female, endophenotype, Genome-Wide Association Study, SNPs, Atrophy, 030217 neurology & neurosurgery
Abstract: BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 × 10(-4)) and white matter volume (R2 = .051, p = 8.6 × 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.
Published: 2013

48. Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Author: Randall, JC, Winkler, TW, Kutalik, Z, Berndt, SI, Jackson, AU, Monda, KL, Kilpeläinen, TO, Esko, T, Mägi, R, Li, S, Workalemahu, T, Feitosa, MF, Croteau-Chonka, DC, Day, FR, Fall, T, Ferreira, T, Gustafsson, S, Locke, AE, Mathieson, I, Scherag, A, Vedantam, S, Wood, AR, Liang, L, Steinthorsdottir, V, Thorleifsson, G, Dermitzakis, ET, Dimas, AS, Karpe, F, Min, JL, Nicholson, G, Clegg, DJ, Person, T, Krohn, JP, Bauer, S, Buechler, C, Eisinger, K, DIAGRAM Consortium, Bonnefond, A, Froguel, P, MAGIC Investigators, Hottenga, JJ, Prokopenko, I, Waite, LL, Harris, TB, Smith, AV, Shuldiner, AR, McArdle, WL, Caulfield, MJ, Munroe, PB, Grönberg, H, Chen, YD, Li, G, Beckmann, JS, Johnson, T, Thorsteinsdottir, U, Teder-Laving, M, Khaw, KT, Wareham, NJ, Zhao, JH, Amin, N, Oostra, BA, Kraja, AT, Province, MA, Cupples, LA, Heard-Costa, NL, Kaprio, J, Ripatti, S, Surakka, I, Collins, FS, Saramies, J, Tuomilehto, J, Jula, A, Salomaa, V, Erdmann, J, Hengstenberg, C, Loley, C, Schunkert, H, Lamina, C, Wichmann, HE, Albrecht, E, Gieger, C, Hicks, AA, Johansson, A, Pramstaller, PP, Kathiresan, S, Speliotes, EK, Penninx, B, Hartikainen, AL, Jarvelin, MR, Gyllensten, U, Boomsma, DI, Campbell, H, Wilson, JF, Chanock, SJ, Farrall, M, Goel, A, Medina-Gomez, C, Rivadeneira, F, Estrada, K, Uitterlinden, AG, Hofman, A, Zillikens, MC, den Heijer, M, Kiemeney, LA, Maschio, A, Hall, P, Tyrer, J, Teumer, A, Völzke, H, Kovacs, P, Tönjes, A, Mangino, M, Spector, TD, Hayward, C, Rudan, I, Hall, AS, Samani, NJ, Attwood, AP, Sambrook, JG, Hung, J, Palmer, LJ, Lokki, ML, Sinisalo, J, Boucher, G, Huikuri, H, Lorentzon, M, Ohlsson, C, Eklund, N, Eriksson, JG, Barlassina, C, Rivolta, C, Nolte, IM, Snieder, H, Van der Klauw, MM, Van Vliet-Ostaptchouk, JV, Gejman, PV, Shi, J, Jacobs, KB, Wang, Z, Bakker, SJ, Mateo Leach, I, Navis, G, van der Harst, P, Martin, NG, Medland, SE, Montgomery, GW, Yang, J, Chasman, DI, Ridker, PM, Rose, LM, Lehtimäki, T, Raitakari, O, Absher, D, Iribarren, C, Basart, H, Hovingh, KG, Hyppönen, E, Power, C, Anderson, D, Beilby, JP, Hui, J, Jolley, J, Sager, H, Bornstein, SR, Schwarz, PE, Kristiansson, K, Perola, M, Lindström, J, Swift, AJ, Uusitupa, M, Atalay, M, Lakka, TA, Rauramaa, R, Bolton, JL, Fowkes, G, Fraser, RM, Price, JF, Fischer, K, Krjutå Kov, K, Metspalu, A, Mihailov, E, Langenberg, C, Luan, J, Ong, KK, Chines, PS, Keinanen-Kiukaanniemi, SM, Saaristo, TE, Edkins, S, Franks, PW, Hallmans, G, Shungin, D, Morris, AD, Palmer, CN, Erbel, R, Moebus, S, Nöthen, MM, Pechlivanis, S, Hveem, K, Narisu, N, Hamsten, A, Humphries, SE, Strawbridge, RJ, Tremoli, E, Grallert, H, Thorand, B, Illig, T, Koenig, W, Müller-Nurasyid, M, Peters, A, Boehm, BO, Kleber, ME, März, W, Winkelmann, BR, Kuusisto, J, Laakso, M, Arveiler, D, Cesana, G, Kuulasmaa, K, Virtamo, J, Yarnell, JW, Kuh, D, Wong, A, Lind, L, de Faire, U, Gigante, B, Magnusson, PK, Pedersen, NL, Dedoussis, G, Dimitriou, M, Kolovou, G, Kanoni, S, Stirrups, K, Bonnycastle, LL, Njølstad, I, Wilsgaard, T, Ganna, A, Rehnberg, E, Hingorani, A, Kivimaki, M, Kumari, M, Assimes, TL, Barroso, I, Boehnke, M, Borecki, IB, Deloukas, P, Fox, CS, Frayling, T, Groop, LC, Haritunians, T, Hunter, D, Ingelsson, E, Kaplan, R, Mohlke, KL, O'Connell, JR, Schlessinger, D, Strachan, DP, Stefansson, K, van Duijn, CM, Abecasis, GR, McCarthy, MI, Hirschhorn, JN, Qi, L, Loos, RJ, Lindgren, CM, North, KE, Heid, IM, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Haartman Institute (-2014), Transplantation Laboratory, Kardiologian yksikkö, Department of Medicine, Clinicum, Department of General Practice and Primary Health Care, Diabetes and Obesity Research Program, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM Consortium, MAGIC Investigators, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Epidemiology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Internal Medicine, Public Health, Surgery, Medical Research Council (MRC), and Dermitzakis, Emmanouil
Subjects: Male, Medicin och hälsovetenskap, Epidemiology, VARIANTS, Anthropometry/methods, Body Height/genetics, Body Mass Index, Body Weight/genetics, Body Weights and Measures, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Sex Characteristics, Waist Circumference/genetics, Waist-Hip Ratio, Medical and Health Sciences, ddc:576.5, GENETICS & HEREDITY, ADULT HEIGHT, RISK, Anthropometry, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, OBESITY, Genetic Epidemiology, Medicine, PPAR-GAMMA, Waist Circumference, Life Sciences & Biomedicine, Medical Genetics, Research Article, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, lcsh:QH426-470, 515 Psychology, education, DIAGRAM Consortium, Endocrinology and Diabetes, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, MAGIC Investigators, ddc:610, ENZYME-ACTIVITIES, METAANALYSIS, Medicinsk genetik, 0604 Genetics, Science & Technology, Body Weight, FAT DISTRIBUTION, Body Height, BODY-MASS INDEX, lcsh:Genetics, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Developmental Biology
Abstract: Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR, Author Summary Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Published: 2013

49. Replication of association between a SLITRK1 haplotype and Tourette Syndrome in a large sample of families

Author: Karagiannidis, I, Rizzo, Renata, Tarnok, Z, Wolanczyk, T, Hebebrand, J, Nöthen, Mm, Lehmkuhl, G, Farkas, L, Nagy, P, Barta, C, Szymanska, U, Panteloglou, G, Miranda, Dm, Feng, Y, Sandor, P, Barr, C, Tsgenesee, and Paschou, P.
Subjects: Family Health, Genetics, Haplotype, Medizin, Membrane Proteins, Nerve Tissue Proteins, Tourette Syndrome, SLITRK gene, Genetic etiology, medicine.disease, SLITRK1, Tourette syndrome, Large sample, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Haplotypes, Replication (statistics), medicine, Genetic Predisposition to Disease, Association (psychology), Psychology, Molecular Biology, Genetic Association Studies
Abstract: Replication of association between a SLITRK1 haplotype and Tourette Syndrome in a large sample of families
Published: 2012

50. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author: Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository
Subjects: Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract: OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.
Published: 2011

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