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3. Genome‐wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response

Author

Wen, CC, Yee, SW, Liang, X, Hoffmann, TJ, Kvale, MN, Banda, Y, Jorgenson, E, Schaefer, C, Risch, N, and Giacomini, KM

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Human Genome, Clinical Research, Genetics, Prevention, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, Aged, Allopurinol, Biomarkers, California, Cell Survival, Dose-Response Relationship, Drug, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Gout Suppressants, HEK293 Cells, Humans, Hyperuricemia, Male, Middle Aged, Mitoxantrone, Neoplasm Proteins, Pharmacogenetics, Phenotype, Polymorphism, Single Nucleotide, Transfection, Treatment Outcome, Uric Acid, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Published
2015

4. Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort

Author

Witte, John, Hoffmann, Thomas, Risch, Neil, Hoffmann, TJ, Sakoda, LC, Shen, L, Jorgenson, E, Habel, LA, Liu, J, Kvale, MN, Asgari, MM, Banda, Y, and Corley, D

Abstract

© 2015 Hoffmann et al.An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of t

Published
2015

5. Detection of identity by descent using next-generation whole genome sequencing data

Author

Baranzini, Sergio, Su, SY, Kasberger, J, Byerley, W, Liao, W, Oksenberg, J, Sherr, E, and Jorgenson, E

Abstract

Background: Identity by descent (IBD) has played a fundamental role in the discovery of genetic loci underlying human diseases. Both pedigree-based and population-based linkage analyses rely on estimating recent IBD, and evidence of ancient IBD can be used

Published
2012

6. Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping

Author

Giacomini, Kathleen, Kroetz, Deanna, Matsson, P, Yee, SW, Markova, S, Morrissey, K, Jenkins, G, Xuan, J, Jorgenson, E, Kroetz, DL, and Giacomini, KM

Abstract

ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic bas

Published
2012

7. Genome-wide meta-analyses of smoking behaviors in African Americans.

Author

David, SP, Hamidovic, A, Chen, GK, Bergen, AW, Wessel, J, Kasberger, JL, Brown, WM, Petruzella, S, Thacker, EL, Kim, Y, Nalls, MA, Tranah, GJ, Sung, YJ, Ambrosone, CB, Arnett, D, Bandera, EV, Becker, DM, Becker, L, Berndt, SI, Bernstein, L, Blot, WJ, Broeckel, U, Buxbaum, SG, Caporaso, N, Casey, G, Chanock, SJ, Deming, SL, Diver, WR, Eaton, CB, Evans, DS, Evans, MK, Fornage, M, Franceschini, N, Harris, TB, Henderson, BE, Hernandez, DG, Hitsman, B, Hu, JJ, Hunt, SC, Ingles, SA, John, EM, Kittles, R, Kolb, S, Kolonel, LN, Le Marchand, L, Liu, Y, Lohman, KK, McKnight, B, Millikan, RC, Murphy, A, Neslund-Dudas, C, Nyante, S, Press, M, Psaty, BM, Rao, DC, Redline, S, Rodriguez-Gil, JL, Rybicki, BA, Signorello, LB, Singleton, AB, Smoller, J, Snively, B, Spring, B, Stanford, JL, Strom, SS, Swan, GE, Taylor, KD, Thun, MJ, Wilson, AF, Witte, JS, Yamamura, Y, Yanek, LR, Yu, K, Zheng, W, Ziegler, RG, Zonderman, AB, Jorgenson, E, Haiman, CA, and Furberg, H

Subjects
Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 15, Humans, Genetic Predisposition to Disease, Proteoglycans, Receptors, Nicotinic, Nerve Tissue Proteins, Smoking, Genotype, Phenotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, African Americans, Female, Male, Statistics as Topic, Genetic Variation, Genome-Wide Association Study, Genetic Loci, African American, genome-wide association, health disparities, nicotine, smoking, tobacco, Chromosomes, Human, Pair 10, Pair 15, Polymorphism, Single Nucleotide, Receptors, Nicotinic, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

Published
2012

8. Common and rare variant associations with clonal haematopoiesis phenotypes

Author

Kessler, M.D., Damask, A., O'Keeffe, S., Banerjee, N., Li, D., Watanabe, K., Marketta, A., VanMeter, M., Horowitz, J., Tang, J., Kosmicki, J.A., Rajagopal, V.M., Zou, Y., Houvras, Y., Ghosh, A., Gilles, C., Mbatchou, J., White, R.R., Verweij, N., Bovijn, J., Parikshak, N.N., LeBlanc, M.G., Jones, M., Glass, D.J., Lotta, L.A., Cantor, M.N., Atwal, G.S., Locke, A.E., Ferreira, M.A.R., Deering, R., Paulding, C., Schuldiner, A.R., Thurston, G., Ferrando, A.A., Salerno, W., Reid, J.G., Overton, J.D., Marchini, J., Kang, H.M., Baras, A., Abecasis, G.R., Jorgenson, E., and Semrau, S.

Subjects
Multidisciplinary, Cardiovascular Diseases, Humans, COVID-19, Clonal Hematopoiesis
Abstract

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes

Published
2022

12. Assessment of Bidirectional Relationships Between Physical Activity and Depression Among Adults A 2-Sample Mendelian Randomization Study

Author

Choi, K.W., Chen, C.Y., Stein, M.B., Klimentidis, Y.C., Wang, M.J., Koenen, K.C., Smoller, J.W., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T., Andlauer, T.F.M., Bacanu, S.A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Hvarregaard, J., Christensen, J.H., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W., Krogh, J., Kutalik, Z., Li, Y.H., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Marchini, J., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Saeed, S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.L.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Nordentoft, M., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Stefansson, K., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Borglum, A.D., Sullivan, P.F., Major Depressive Disorder Working, Epidemiology, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Psychiatry, Biological Psychology, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and Adult Psychiatry

Subjects
Adult, DISORDER, medicine.medical_specialty, Genome-wide association study, EXERCISE, CAUSALITY, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, PEOPLE, Internal medicine, Accelerometry, Mendelian randomization, SCHIZOPHRENIA, Humans, Medicine, ANXIETY, Exercise, RISK, Depressive Disorder, Major, business.industry, Case-control study, SEDENTARY BEHAVIOR, Mendelian Randomization Analysis, Odds ratio, ASSOCIATION, Protective Factors, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Sample size determination, Case-Control Studies, Meta-analysis, Major depressive disorder, Self Report, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Importance: Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.Objective: To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.Design, Setting, and Participants: This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.Main Outcomes and Measures: MDD and physical activity.Results: GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).Conclusions and Relevance: Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.

Published
2019

13. A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Author

Hardcastle, A.J., Liskova, P., Bykhovskaya, Y., McComish, B.J., Davidson, A.E., Inglehearn, C.F., Li, X, Choquet, H., Habeeb, M., Lucas, S.E.M., Sahebjada, S., Pontikos, N., Lopez, K.E.R., Khawaja, A.P., Ali, M, Dudakova, L., Skalicka, P., Dooren, B.T.H. van, Geerards, A.J., Haudum, C.W., Faro, V.L., Tenen, A., Simcoe, M.J., Patasova, K., Yarrand, D., Yin, J., Siddiqui, S., Rice, A., Farraj, L.A., Chen, Yi, Rahi, J.S., Krauss, R.M., Theusch, E., Charlesworth, J.C., Szczotka-Flynn, L., Toomes, C., Meester-Smoor, M.A., Richardson, A.J., Mitchell, P.A., Taylor, K.D., Melles, R.B., Aldave, A.J., Mills, R.A., Cao, K., Chan, E., Daniell, M.D., Wang, J.J., Rotter, J.I., Hewitt, A.W., MacGregor, S., Klaver, C.C.W., Ramdas, W.D., Craig, J.E., Iyengar, S.K., O'Brart, D., Jorgenson, E., Baird, P.N., Rabinowitz, Y.S., Burdon, K.P., Hammond, C.J., Tuft, S.J., Hysi, P.G., Hardcastle, A.J., Liskova, P., Bykhovskaya, Y., McComish, B.J., Davidson, A.E., Inglehearn, C.F., Li, X, Choquet, H., Habeeb, M., Lucas, S.E.M., Sahebjada, S., Pontikos, N., Lopez, K.E.R., Khawaja, A.P., Ali, M, Dudakova, L., Skalicka, P., Dooren, B.T.H. van, Geerards, A.J., Haudum, C.W., Faro, V.L., Tenen, A., Simcoe, M.J., Patasova, K., Yarrand, D., Yin, J., Siddiqui, S., Rice, A., Farraj, L.A., Chen, Yi, Rahi, J.S., Krauss, R.M., Theusch, E., Charlesworth, J.C., Szczotka-Flynn, L., Toomes, C., Meester-Smoor, M.A., Richardson, A.J., Mitchell, P.A., Taylor, K.D., Melles, R.B., Aldave, A.J., Mills, R.A., Cao, K., Chan, E., Daniell, M.D., Wang, J.J., Rotter, J.I., Hewitt, A.W., MacGregor, S., Klaver, C.C.W., Ramdas, W.D., Craig, J.E., Iyengar, S.K., O'Brart, D., Jorgenson, E., Baird, P.N., Rabinowitz, Y.S., Burdon, K.P., Hammond, C.J., Tuft, S.J., and Hysi, P.G.

Abstract

Contains fulltext : 243900.pdf (Publisher’s version ) (Open Access), Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Published
2021

14. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, P., Jorgenson, E., Hysi, P., Khawaja, A.P., Pendergrass, S., Han, X., Ong, J.S., Hewitt, A.W., Segrè, A.V., Rouhana, J.M., Hamel, A.R., Igo, R.P., Jr., Choquet, H., Qassim, A., Josyula, N.S., Bailey, J.N., Bonnemaijer, P.W.M., Iglesias, A., Siggs, O.M., Young, T.L., Vitart, V., Thiadens, A., Karjalainen, J., Uebe, S., Melles, R.B., Nair, K.S., Luben, R., Simcoe, M., Amersinghe, N., Cree, A.J., Hohn, R., Poplawski, A., Chen, L.J., Rong, S.S., Aung, T., Vithana, E.N., Tamiya, G., Shiga, Y., Yamamoto, M., Nakazawa, T., Currant, H., Birney, E., Wang, X, Auton, A., Lupton, M.K., Martin, N.G., Ashaye, A., Olawoye, O., Williams, S.E., Akafo, S., Ramsay, M., Hashimoto, K., Kamatani, Y., Akiyama, M., Momozawa, Y., Foster, P.J., Khaw, P.T., Morgan, J.E., Strouthidis, N.G., Kraft, P., Kang, J.H., Pang, C.P., Pasutto, F., Mitchell, P., Lotery, A.J., Palotie, A., Duijn, C. van, Haines, J.L., Hammond, C., Pasquale, L.R., Klaver, C.C.W., Hauser, M., Khor, C.C., Mackey, D.A., Kubo, M., Cheng, C.Y., Craig, J.E., MacGregor, S., Wiggs, J.L., Gharahkhani, P., Jorgenson, E., Hysi, P., Khawaja, A.P., Pendergrass, S., Han, X., Ong, J.S., Hewitt, A.W., Segrè, A.V., Rouhana, J.M., Hamel, A.R., Igo, R.P., Jr., Choquet, H., Qassim, A., Josyula, N.S., Bailey, J.N., Bonnemaijer, P.W.M., Iglesias, A., Siggs, O.M., Young, T.L., Vitart, V., Thiadens, A., Karjalainen, J., Uebe, S., Melles, R.B., Nair, K.S., Luben, R., Simcoe, M., Amersinghe, N., Cree, A.J., Hohn, R., Poplawski, A., Chen, L.J., Rong, S.S., Aung, T., Vithana, E.N., Tamiya, G., Shiga, Y., Yamamoto, M., Nakazawa, T., Currant, H., Birney, E., Wang, X, Auton, A., Lupton, M.K., Martin, N.G., Ashaye, A., Olawoye, O., Williams, S.E., Akafo, S., Ramsay, M., Hashimoto, K., Kamatani, Y., Akiyama, M., Momozawa, Y., Foster, P.J., Khaw, P.T., Morgan, J.E., Strouthidis, N.G., Kraft, P., Kang, J.H., Pang, C.P., Pasutto, F., Mitchell, P., Lotery, A.J., Palotie, A., Duijn, C. van, Haines, J.L., Hammond, C., Pasquale, L.R., Klaver, C.C.W., Hauser, M., Khor, C.C., Mackey, D.A., Kubo, M., Cheng, C.Y., Craig, J.E., MacGregor, S., and Wiggs, J.L.

Abstract

Contains fulltext : 235429.pdf (Publisher’s version ) (Open Access), Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Published
2021

15. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Author

Currant, H., Hysi, P., Fitzgerald, T.W., Gharahkhani, P., Bonnemaijer, P.W.M., Senabouth, A., Hewitt, A.W., Atan, D., Aung, T., Charng, J., Choquet, H., Craig, J., Khaw, P.T., Klaver, C.C.W., Kubo, M., Ong, J.S., Pasquale, L.R., Reisman, C.A., Daniszewski, M., Powell, J.E., Pébay, A., Simcoe, M.J., Thiadens, A., Duijn, C.M. van, Yazar, S., Jorgenson, E., MacGregor, S., Hammond, C.J., Mackey, D.A., Wiggs, J.L., Foster, P.J., Patel, P.J., Birney, E., Khawaja, A.P., Currant, H., Hysi, P., Fitzgerald, T.W., Gharahkhani, P., Bonnemaijer, P.W.M., Senabouth, A., Hewitt, A.W., Atan, D., Aung, T., Charng, J., Choquet, H., Craig, J., Khaw, P.T., Klaver, C.C.W., Kubo, M., Ong, J.S., Pasquale, L.R., Reisman, C.A., Daniszewski, M., Powell, J.E., Pébay, A., Simcoe, M.J., Thiadens, A., Duijn, C.M. van, Yazar, S., Jorgenson, E., MacGregor, S., Hammond, C.J., Mackey, D.A., Wiggs, J.L., Foster, P.J., Patel, P.J., Birney, E., and Khawaja, A.P.

Abstract

Contains fulltext : 235428.pdf (Publisher’s version ) (Open Access), Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Published
2021

16. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Author

Hauser, MA, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, Khawaja, AP, Hauser, MA, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, and Khawaja, AP

Abstract

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

Published
2021

17. A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Author

Hardcastle, AJ, Liskova, P, Bykhovskaya, Y, McComish, BJ, Davidson, AE, Inglehearn, CF, Li, X, Choquet, H, Habeeb, M, Lucas, SEM, Sahebjada, S, Pontikos, N, Lopez, KER, Khawaja, AP, Ali, M, Dudakova, L, Skalicka, P, Van Dooren, BTH, Geerards, AJM, Haudum, CW, Lo Faro, V, Tenen, A, Simcoe, MJ, Patasova, K, Yarrand, D, Yin, J, Siddiqui, S, Rice, A, Farraj, LA, Chen, Y-DI, Rahi, JS, Krauss, RM, Theusch, E, Charlesworth, JC, Szczotka-Flynn, L, Toomes, C, Meester-Smoor, MA, Richardson, AJ, Mitchell, PA, Taylor, KD, Melles, RB, Aldave, AJ, Mills, RA, Cao, K, Chan, E, Daniell, MD, Wang, JJ, Rotter, JI, Hewitt, AW, MacGregor, S, Klaver, CCW, Ramdas, WD, Craig, JE, Iyengar, SK, O'Brart, D, Jorgenson, E, Baird, PN, Rabinowitz, YS, Burdon, KP, Hammond, CJ, Tuft, SJ, Hysi, PG, Hardcastle, AJ, Liskova, P, Bykhovskaya, Y, McComish, BJ, Davidson, AE, Inglehearn, CF, Li, X, Choquet, H, Habeeb, M, Lucas, SEM, Sahebjada, S, Pontikos, N, Lopez, KER, Khawaja, AP, Ali, M, Dudakova, L, Skalicka, P, Van Dooren, BTH, Geerards, AJM, Haudum, CW, Lo Faro, V, Tenen, A, Simcoe, MJ, Patasova, K, Yarrand, D, Yin, J, Siddiqui, S, Rice, A, Farraj, LA, Chen, Y-DI, Rahi, JS, Krauss, RM, Theusch, E, Charlesworth, JC, Szczotka-Flynn, L, Toomes, C, Meester-Smoor, MA, Richardson, AJ, Mitchell, PA, Taylor, KD, Melles, RB, Aldave, AJ, Mills, RA, Cao, K, Chan, E, Daniell, MD, Wang, JJ, Rotter, JI, Hewitt, AW, MacGregor, S, Klaver, CCW, Ramdas, WD, Craig, JE, Iyengar, SK, O'Brart, D, Jorgenson, E, Baird, PN, Rabinowitz, YS, Burdon, KP, Hammond, CJ, Tuft, SJ, and Hysi, PG

Abstract

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Published
2021

18. Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images (vol 17, e1009497, 2021)

Author

Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, Khawaja, AP, Currant, H, Hysi, P, Fitzgerald, TW, Gharahkhani, P, Bonnemaijer, PWM, Senabouth, A, Hewitt, AW, Atan, D, Aung, T, Charng, J, Choquet, H, Craig, J, Khaw, PT, Klaver, CCW, Kubo, M, Ong, J-S, Pasquale, LR, Reisman, CA, Daniszewski, M, Powell, JE, Pebay, A, Simcoe, MJ, Thiadens, AAHJ, van Duijn, CM, Yazar, S, Jorgenson, E, MacGregor, S, Hammond, CJ, Mackey, DA, Wiggs, JL, Foster, PJ, Patel, PJ, Birney, E, and Khawaja, AP

Abstract

[This corrects the article DOI: 10.1371/journal.pgen.1009497.].

Published
2021

19. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, Wiggs, JL, Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, and Wiggs, JL

Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Published
2021

20. Large-Scale Imputation of KIR Copy Number and HLA Alleles in North American and European Psoriasis Case-Control Cohorts Reveals Association of Inhibitory KIR2DL2 With Psoriasis

Author

Ahn, R, Vukcevic, D, Motyer, A, Nititham, J, Squire, DM, Hollenbach, JA, Norman, PJ, Ellinghaus, E, Nair, RP, Tsoi, LC, Oksenberg, J, Foerster, J, Lieb, W, Weidinger, S, Franke, A, Elder, JT, Jorgenson, E, Leslie, S, Liao, W, Ahn, R, Vukcevic, D, Motyer, A, Nititham, J, Squire, DM, Hollenbach, JA, Norman, PJ, Ellinghaus, E, Nair, RP, Tsoi, LC, Oksenberg, J, Foerster, J, Lieb, W, Weidinger, S, Franke, A, Elder, JT, Jorgenson, E, Leslie, S, and Liao, W

Abstract

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.

Published
2021

22. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Hysi, P.G., Choquet, Helene, Khawaja, A.P., Wojciechowski, R., Tedja, M.S., Yin, Jie, Klaver, C.C.W., Jorgenson, E., Hammond, C.J., Hysi, P.G., Choquet, Helene, Khawaja, A.P., Wojciechowski, R., Tedja, M.S., Yin, Jie, Klaver, C.C.W., Jorgenson, E., and Hammond, C.J.

Abstract

Contains fulltext : 217764.pdf (Publisher’s version ) (Closed access)

Published
2020

23. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Vuckovic, D. (Dragana), Bao, E.L. (Erik L.), Akbari, P. (Parsa), Lareau, C.A. (Caleb A.), Mousas, A. (Abdou), Jiang, T. (Tao), Chen, M.-H. (Ming-Huei), Raffield, L.M. (Laura M.), Tardaguila, M. (Manuel), Huffman, J.E. (Jennifer E.), Ritchie, S.C. (Scott C.), Megy, K. (Karyn), Ponstingl, H. (Hannes), Penkett, C.J. (Christopher J.), Albers, P.K. (Patrick K.), Wigdor, E.M. (Emilie M.), Sakaue, S. (Saori), Moscati, A. (Arden), Manansala, R. (Regina), Lo, K.S., Qian, H. (Huijun), Akiyama, M. (Masato), Bartz, T.M. (Traci M.), Ben-Shlomo, Y. (Yoav), Beswick, A. (Andrew), Bork-Jensen, J. (Jette), Bottinger, E.P. (Erwin), Brody, J.A. (Jennifer A.), Rooij, F.J.A. (Frank) van, Chitrala, K.N. (Kumaraswamy N.), Wilson, P.W.F. (Peter W.F.), Choquet, H. (Hélène), Danesh, J. (John), Angelantonio, E. (Emanuele) di, Dimou, N. (Niki), Ding, J. (Jingzhong), Elliott, P. (Paul), Esko, T. (Tõnu), Evans, M.K. (Michele), Felix, S.B. (Stephan Burkhard), Floyd, J.S. (James S.), Broer, L. (Linda), Grarup, N. (Niels), Guo, M.H. (Michael H.), Guo, Q. (Qi), Greinacher, A. (Andreas), Haessler, J. (Jeff), Hansen, T. (Torben), Howson, J.M.M. (Joanna M.M.), Huang, W. (Wei), Jorgenson, E. (Eric), Kacprowski, T. (Tim), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Karthikeyan, S. (Savita), Koskeridis, F. (Fotios), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Liu, Y. (YongMei), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Matsuda, K. (Koichi), Mohlke, K.L. (Karen L.), Mononen, N. (Nina), Murakami, Y. (Yoshinori), Nadkarni, G. (Girish), Nikus, K. (Kjell), Pankratz, V.S. (Shane), Pedersen, O. (Oluf), Preuss, M. (Michael), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Rich, S.S. (Stephen), Rodriguez, B.A.T. (Benjamin A.T.), Rosen, J.D. (Jonathan D.), Rotter, J.I. (Jerome I.), Schubert, P. (Petra), Spracklen, C.N. (Cassandra N.), Surendran, P. (Praveen), Tang, H. (Hua), Tardif, J.-C. (Jean-Claude), Ghanbari, M. (Mohsen), Völker, U. (Uwe), Völzke, H. (Henry), Watkins, N.A. (Nicholas A.), Weiss, S. (Stefan), Cai, N. (Na), Kundu, K. (Kousik), Watt, S.B. (Stephen B.), Walter, K. (Klaudia), Zonderman, A.B. (Alan B.), Cho, K. (Kelly), Li, Y. (Yun), Loos, R.J.F. (Ruth), Knight, J.C. (Julian), Georges, M. (Michel), Stegle, O. (Oliver), Evangelou, E. (Evangelos), Okada, Y. (Yukinori), Roberts, D.J. (David J.), Inouye, M. (Michael), Johnson, A.D. (Andrew), Auer, P.L. (Paul L.), Astle, W.J. (William J.), Reiner, A.P. (Alexander P.), Butterworth, A.S. (Adam S.), Ouwehand, W.H. (Willem), Lettre, G. (Guillaume), Sankaran, V.G. (Vijay G.), Soranzo, N. (Nicole), Vuckovic, D. (Dragana), Bao, E.L. (Erik L.), Akbari, P. (Parsa), Lareau, C.A. (Caleb A.), Mousas, A. (Abdou), Jiang, T. (Tao), Chen, M.-H. (Ming-Huei), Raffield, L.M. (Laura M.), Tardaguila, M. (Manuel), Huffman, J.E. (Jennifer E.), Ritchie, S.C. (Scott C.), Megy, K. (Karyn), Ponstingl, H. (Hannes), Penkett, C.J. (Christopher J.), Albers, P.K. (Patrick K.), Wigdor, E.M. (Emilie M.), Sakaue, S. (Saori), Moscati, A. (Arden), Manansala, R. (Regina), Lo, K.S., Qian, H. (Huijun), Akiyama, M. (Masato), Bartz, T.M. (Traci M.), Ben-Shlomo, Y. (Yoav), Beswick, A. (Andrew), Bork-Jensen, J. (Jette), Bottinger, E.P. (Erwin), Brody, J.A. (Jennifer A.), Rooij, F.J.A. (Frank) van, Chitrala, K.N. (Kumaraswamy N.), Wilson, P.W.F. (Peter W.F.), Choquet, H. (Hélène), Danesh, J. (John), Angelantonio, E. (Emanuele) di, Dimou, N. (Niki), Ding, J. (Jingzhong), Elliott, P. (Paul), Esko, T. (Tõnu), Evans, M.K. (Michele), Felix, S.B. (Stephan Burkhard), Floyd, J.S. (James S.), Broer, L. (Linda), Grarup, N. (Niels), Guo, M.H. (Michael H.), Guo, Q. (Qi), Greinacher, A. (Andreas), Haessler, J. (Jeff), Hansen, T. (Torben), Howson, J.M.M. (Joanna M.M.), Huang, W. (Wei), Jorgenson, E. (Eric), Kacprowski, T. (Tim), Kähönen, M. (Mika), Kamatani, Y. (Yoichiro), Kanai, M. (Masahiro), Karthikeyan, S. (Savita), Koskeridis, F. (Fotios), Lange, L.A. (Leslie A.), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Liu, Y. (YongMei), Lyytikäinen, L.-P. (Leo-Pekka), Manichaikul, A. (Ani), Matsuda, K. (Koichi), Mohlke, K.L. (Karen L.), Mononen, N. (Nina), Murakami, Y. (Yoshinori), Nadkarni, G. (Girish), Nikus, K. (Kjell), Pankratz, V.S. (Shane), Pedersen, O. (Oluf), Preuss, M. (Michael), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Rich, S.S. (Stephen), Rodriguez, B.A.T. (Benjamin A.T.), Rosen, J.D. (Jonathan D.), Rotter, J.I. (Jerome I.), Schubert, P. (Petra), Spracklen, C.N. (Cassandra N.), Surendran, P. (Praveen), Tang, H. (Hua), Tardif, J.-C. (Jean-Claude), Ghanbari, M. (Mohsen), Völker, U. (Uwe), Völzke, H. (Henry), Watkins, N.A. (Nicholas A.), Weiss, S. (Stefan), Cai, N. (Na), Kundu, K. (Kousik), Watt, S.B. (Stephen B.), Walter, K. (Klaudia), Zonderman, A.B. (Alan B.), Cho, K. (Kelly), Li, Y. (Yun), Loos, R.J.F. (Ruth), Knight, J.C. (Julian), Georges, M. (Michel), Stegle, O. (Oliver), Evangelou, E. (Evangelos), Okada, Y. (Yukinori), Roberts, D.J. (David J.), Inouye, M. (Michael), Johnson, A.D. (Andrew), Auer, P.L. (Paul L.), Astle, W.J. (William J.), Reiner, A.P. (Alexander P.), Butterworth, A.S. (Adam S.), Ouwehand, W.H. (Willem), Lettre, G. (Guillaume), Sankaran, V.G. (Vijay G.), and Soranzo, N. (Nicole)

Abstract

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation. Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.

Published
2020
Full Text
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24. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author

Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, Borglum, AD, Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, and Borglum, AD

Abstract

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Published
2020

25. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Vuckovic, D, Bao, EL, Akbari, P, Lareau, CA, Mousas, A, Jiang, T, Chen, M-H, Raffield, LM, Tardaguila, M, Huffman, JE, Ritchie, SC, Megy, K, Ponstingl, H, Penkett, CJ, Albers, PK, Wigdor, EM, Sakaue, S, Moscati, A, Manansala, R, Lo, KS, Qian, H, Akiyama, M, Bartz, TM, Ben-Shlomo, Y, Beswick, A, Bork-Jensen, J, Bottinger, EP, Brody, JA, van Rooij, FJA, Chitrala, KN, Wilson, PWF, Choquet, H, Danesh, J, Di Angelantonio, E, Dimou, N, Ding, J, Elliott, P, Esko, T, Evans, MK, Felix, SB, Floyd, JS, Broer, L, Grarup, N, Guo, MH, Guo, Q, Greinacher, A, Haessler, J, Hansen, T, Howson, JMM, Huang, W, Jorgenson, E, Kacprowski, T, Kahonen, M, Kamatani, Y, Kanai, M, Karthikeyan, S, Koskeridis, F, Lange, LA, Lehtimaki, T, Linneberg, A, Liu, Y, Lyytikainen, L-P, Manichaikul, A, Matsuda, K, Mohlke, KL, Mononen, N, Murakami, Y, Nadkarni, GN, Nikus, K, Pankratz, N, Pedersen, O, Preuss, M, Psaty, BM, Raitakari, OT, Rich, SS, Rodriguez, BAT, Rosen, JD, Rotter, JI, Schubert, P, Spracklen, CN, Surendran, P, Tang, H, Tardif, J-C, Ghanbari, M, Volker, U, Volzke, H, Watkins, NA, Weiss, S, Cai, N, Kundu, K, Watt, SB, Walter, K, Zonderman, AB, Cho, K, Li, Y, Loos, RJF, Knight, JC, Georges, M, Stegle, O, Evangelou, E, Okada, Y, Roberts, DJ, Inouye, M, Johnson, AD, Auer, PL, Astle, WJ, Reiner, AP, Butterworth, AS, Ouwehand, WH, Lettre, G, Sankaran, VG, Soranzo, N, Vuckovic, D, Bao, EL, Akbari, P, Lareau, CA, Mousas, A, Jiang, T, Chen, M-H, Raffield, LM, Tardaguila, M, Huffman, JE, Ritchie, SC, Megy, K, Ponstingl, H, Penkett, CJ, Albers, PK, Wigdor, EM, Sakaue, S, Moscati, A, Manansala, R, Lo, KS, Qian, H, Akiyama, M, Bartz, TM, Ben-Shlomo, Y, Beswick, A, Bork-Jensen, J, Bottinger, EP, Brody, JA, van Rooij, FJA, Chitrala, KN, Wilson, PWF, Choquet, H, Danesh, J, Di Angelantonio, E, Dimou, N, Ding, J, Elliott, P, Esko, T, Evans, MK, Felix, SB, Floyd, JS, Broer, L, Grarup, N, Guo, MH, Guo, Q, Greinacher, A, Haessler, J, Hansen, T, Howson, JMM, Huang, W, Jorgenson, E, Kacprowski, T, Kahonen, M, Kamatani, Y, Kanai, M, Karthikeyan, S, Koskeridis, F, Lange, LA, Lehtimaki, T, Linneberg, A, Liu, Y, Lyytikainen, L-P, Manichaikul, A, Matsuda, K, Mohlke, KL, Mononen, N, Murakami, Y, Nadkarni, GN, Nikus, K, Pankratz, N, Pedersen, O, Preuss, M, Psaty, BM, Raitakari, OT, Rich, SS, Rodriguez, BAT, Rosen, JD, Rotter, JI, Schubert, P, Spracklen, CN, Surendran, P, Tang, H, Tardif, J-C, Ghanbari, M, Volker, U, Volzke, H, Watkins, NA, Weiss, S, Cai, N, Kundu, K, Watt, SB, Walter, K, Zonderman, AB, Cho, K, Li, Y, Loos, RJF, Knight, JC, Georges, M, Stegle, O, Evangelou, E, Okada, Y, Roberts, DJ, Inouye, M, Johnson, AD, Auer, PL, Astle, WJ, Reiner, AP, Butterworth, AS, Ouwehand, WH, Lettre, G, Sankaran, VG, and Soranzo, N

Abstract

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

Published
2020

26. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

Author

Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, Sullivan, PF, Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, and Sullivan, PF

Abstract

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Published
2020

27. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Hysi, PG, Choquet, H, Khawaja, AP, Wojciechowski, R, Tedja, MS, Yin, J, Simcoe, MJ, Patasova, K, Mahroo, OA, Thai, KK, Cumberland, PM, Melles, RB, Verhoeven, VJM, Vitart, V, Segre, A, Stone, RA, Wareham, N, Hewitt, AW, Mackey, DA, Klaver, CCW, MacGregor, S, Khaw, PT, Foster, PJ, Guggenheim, JA, Rahi, JS, Jorgenson, E, Hammond, CJ, Hysi, PG, Choquet, H, Khawaja, AP, Wojciechowski, R, Tedja, MS, Yin, J, Simcoe, MJ, Patasova, K, Mahroo, OA, Thai, KK, Cumberland, PM, Melles, RB, Verhoeven, VJM, Vitart, V, Segre, A, Stone, RA, Wareham, N, Hewitt, AW, Mackey, DA, Klaver, CCW, MacGregor, S, Khaw, PT, Foster, PJ, Guggenheim, JA, Rahi, JS, Jorgenson, E, and Hammond, CJ

Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.

Published
2020

31. A Polygenic Risk Score for Asthma in a Large Multi-Ethnic Population

Author

Sordillo, J., primary, Lutz, S.M., additional, Jorgenson, E., additional, Iribarren, C., additional, McGeachie, M., additional, Dahlin, A., additional, Tantisira, K.G., additional, Kelly, R.S., additional, Lasky-Su, J.A., additional, Sakornsakoplat, P., additional, Moll, M., additional, Cho, M.H., additional, and Wu, A.C., additional

Published
2020
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32. Identification of common genetic risk variants for autism spectrum disorder

Author

Grove, J., Ripke, S., Als, T.D., Mattheisen, M., Walters, R.K., Won, H., Pallesen, J., Agerbo, E., Andreassen, O.A., Anney, R., Awashti, S., Belliveau, R., Bettella, F., Buxbaum, J.D., Bybjerg-Grauholm, J., Baekvad-Hansen, M., Cerrato, F., Chambert, K., Christensen, J.H., Churchhouse, C., Dellenvall, K., Demontis, D., Rubeis, S. de, Devlin, B., Djurovic, S., Dumont, A.L., Goldstein, J.I., Hansen, C.S., Hauberg, M.E., Hollegaard, M.V., Hope, S., Howrigan, D.P., Huang, H., Hultman, C.M., Klei, L., Maller, J., Martin, J., Martin, A.R., Moran, J.L., Nyegaard, M., Naeland, T., Palmer, D.S., Palotie, A., Pedersen, C.B., Pedersen, M.G., dPoterba, T., Poulsen, J.B., St Pourcain, B., Qvist, P., Rehnstrom, K., Reichenberg, A., Reichert, J., Robinson, E.B., Roeder, K., Roussos, P., Saemundsen, E., Sandin, S., Satterstrom, F.K., Smith, G.D., Stefansson, H., Steinberg, S., Stevens, C.R., Sullivan, P.F., Turley, P., Walters, G.B., Xu, X.Y., Stefansson, K., Geschwind, D.H., Nordentoft, M., Hougaard, D.M., Werge, T., Mors, O., Mortensen, P.B., Neale, B.M., Daly, M.J., Borglum, A.D., Wray, N.R., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Cai, N., Castelao, E., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Hall, L.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Ising, M., Jansen, R., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Muller-Myhsok, B., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Lewis, C.M., Levinson, D.F., Breen, G., Agee, M., Alipanahi, B., Auton, A., Bell, R.K., Bryc, K., Elson, S.L., Fontanillas, P., Furlotte, N.A., Hromatka, B.S., Huber, K.E., Kleinman, A., Litterman, N.K., McIntyre, M.H., Mountain, J.L., Noblin, E.S., Northover, C.A.M., Pitts, S.J., Sathirapongsasuti, J.F., Sazonova, O.V., Shelton, J.F., Shringarpure, S., Tung, J.Y., Vacic, V., Wilson, C.H., Psychiat Genomics Consortium, BUPGEN, 23andMe Re, Biological Psychology, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, Psychiatry, Human genetics, Amsterdam Reproduction & Development (AR&D), VU University medical center, APH - Digital Health, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Me Research Team, Epidemiology, and Child and Adolescent Psychiatry / Psychology

Subjects
Male, Netherlands Twin Register (NTR), Multifactorial Inheritance, Autism Spectrum Disorder, Denmark, LD SCORE REGRESSION, LOCI, Genome-wide association study, DE-NOVO, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, SYNAPTIC PLASTICITY, CELL-SURFACE, Child, Genetics, 0303 health sciences, HERITABILITY, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Polymorphism, Single Nucleotide/genetics, Phenotype, 3. Good health, Schizophrenia, Autism spectrum disorder, Child, Preschool, Genome-Wide Association Study/methods, Female, SIMONS SIMPLEX COLLECTION, Adolescent, Biology, NEURITE OUTGROWTH, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, 03 medical and health sciences, mental disorders, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, SDG 2 - Zero Hunger, Multifactorial Inheritance/genetics, METAANALYSIS, 030304 developmental biology, Case-control study, Heritability, medicine.disease, Autism Spectrum Disorder/genetics, Case-Control Studies, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Published in final edited form as: Nat Genet. 2019 March ; 51(3): 431–444. doi:10.1038/s41588-019-0344-8., Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture, we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD., The iPSYCH project is funded by the Lundbeck Foundation (grant numbers R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH and PGC samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to MJD), and NIMH (5U01MH094432–02 to MJD). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis on the GenomeDK HPC facility was supported by NIMH (1U01MH109514–01 to M O’Donovan and ADB). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). Drs. S De Rubeis and JD Buxbaum were supported by NIH grants MH097849 (to JDB) and MH111661 (to JDB), and by the Seaver Foundation (to SDR and JDB). Dr J Martin was supported by the Wellcome Trust (grant no: 106047). O. Andreassen received funding from Research Council of Norway (#213694, #223273, #248980, #248778), Stiftelsen KG Jebsen and South-East Norway Health Authority. We thank the research participants and employees of 23andMe for making this work possible.

Published
2019

33. Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Author

Arnau-Soler, A., Macdonald-Dunlop, E., Adams, M.J., Clarke, T.K., MacIntyre, D.J., Milburn, K., Navrady, L., Hayward, C., McIntosh, A.M., Thomson, P.A., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Agerbo, E., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenscon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Rawford, G.E.C., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Foo, J.C., Forstner, A.J., Frank, J., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y.H., Lind, P.A., Macintyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Streit, F., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thorgeirsson, T.E., Traylor, M., Treutlein, J., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y.P., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Witt, S.H., Wu, Y., Xi, H.L.S., Yang, J., Zhang, F.T., Arolt, V., Baune, B.T., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., Metspalu, A., Mors, O., Mortensen, P.B., Muller-Myhsok, B., Nordentoft, M., Nothen, M.M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Rietschel, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Volzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Borglum, A.S.D., Sullivan, P.F., Generation Scotland, and Psychiat Genomics Consortium

Abstract

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

Published
2019

34. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author

Liu, M, Jiang, Y, Wedow, R, Li, Y, Brazel, DM, Chen, F, Datta, G, Davila-Velderrain, J, McGuire, D, Tian, C, Zhan, X, Team, 23Andme Research, Psychiatry, Hunt All-In, Choquet, H, Docherty, AR, Faul, JD, Foerster, JR, Fritsche, LG, Gabrielsen, ME, Gordon, SD, Haessler, J, Hottenga, J-J, Huang, H, Jang, S-K, Jansen, PR, Ling, Y, Mägi, R, Matoba, N, McMahon, G, Mulas, A, Orrù, V, Palviainen, T, Pandit, A, Reginsson, GW, Skogholt, AH, Smith, JA, Taylor, AE, Turman, C, Willemsen, G, Young, H, Young, KA, Zajac, GJM, Zhao, W, Zhou, W, Bjornsdottir, G, Boardman, JD, Boehnke, M, Boomsma, DI, Chen, C, Cucca, F, Davies, GE, Eaton, CB, Ehringer, MA, Esko, T, Fiorillo, E, Gillespie, NA, Gudbjartsson, DF, Haller, T, Harris, KM, Heath, AC, Hewitt, JK, Hickie, IB, Hokanson, JE, Hopfer, CJ, Hunter, DJ, Iacono, WG, Johnson, EO, Kamatani, Y, Kardia, SLR, Keller, MC, Kellis, M, Kooperberg, C, Kraft, P, Krauter, KS, Laakso, M, Lind, PA, Loukola, A, Lutz, SM, Madden, PAF, Martin, NG, McGue, M, McQueen, MB, Medland, SE, Metspalu, A, Mohlke, KL, Nielsen, JB, Okada, Y, Peters, U, Polderman, TJC, Posthuma, D, Reiner, AP, Rice, JP, Rimm, E, Rose, RJ, Runarsdottir, V, Stallings, MC, Stančáková, A, Stefansson, H, Thai, KK, Tindle, HA, Tyrfingsson, T, Wall, TL, Weir, DR, Weisner, C, Whitfield, JB, Winsvold, BS, Yin, J, Zuccolo, L, Bierut, LJ, Hveem, K, Lee, JJ, Munafò, MR, Saccone, NL, Willer, CJ, Cornelis, MC, David, SP, Hinds, DA, Jorgenson, E, Kaprio, J, Stitzel, JA, Stefansson, K, Thorgeirsson, TE, Abecasis, G, Liu, DJ, Vrieze, S, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, APH - Methodology, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Aging & Later Life, and Human Genetics

Subjects
Male, Netherlands Twin Register (NTR), Smoking/genetics, ved/biology.organism_classification_rank.species, Alcohol, Genome-wide association study, Brain and Behaviour, chemistry.chemical_compound, 0302 clinical medicine, Tobacco Use Disorder/genetics, Tobacco/adverse effects, Genetics, 0303 health sciences, Smoking, Tobacco and Alcohol, public health, Tobacco Use Disorder, Middle Aged, 3. Good health, Phenotype, psychiatric disorders, Genetic Variation/genetics, Meta-analysis, Genome-Wide Association Study/methods, Female, Physical and Mental Health, Risk, Alcohol Drinking, psychology, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Tobacco, Humans, Model organism, Gene, 030304 developmental biology, Genetic association, ved/biology, Genetic Variation, Alcohol Drinking/genetics, Heritability, chemistry, genome-wide association studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6,7,8,9,10,11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures. © 2019. This is the authors’ accepted and refereed manuscript to the article.

Published
2019

35. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Author

Foo, J.C., Streit, F., Frank, J., Witt, S.H., Treutlein, J., Baune, B.T., Moebus, S., Jockel, K.H., Forstner, A.J., Nothen, M.M., Rietschel, M., Sartorius, A., Kranaster, L., Wray, N.R., Ripke, S., Mattheisen, M., Trzaskowski, M., Byrne, E.M., Abdellaoui, A., Adams, M.J., Agerbo, E., Air, T.M., Andlauer, T.F.M., Bacanu, S.A., Baekvad-Hansen, M., Beekman, A.T.F., Bigdeli, T.B., Binder, E.B., Blackwood, D.H.R., Bryois, J., Buttenschon, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E., Christensen, J.H., Clarke, T.K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N., Crawford, G.E., Davies, G., Deary, I.J., Degenhardt, F., Derks, E.M., Direk, N., Dolan, C.V., Dunn, E.C., Eley, T.C., Escott-Price, V., Kiadeh, F.F.H., Finucane, H.K., Gaspar, H.A., Gill, M., Goes, F.S., Gordon, S.D., Grove, J., Hall, L.S., Hansen, C.S., Hansen, T.F., Herms, S., Hickie, I.B., Hoffmann, P., Homuth, G., Horn, C., Hottenga, J.J., Hougaard, D.M., Ising, M., Jansen, R., Jones, I., Jones, L.A., Jorgenson, E., Knowles, J.A., Kohane, I.S., Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z., Li, Y.H., Lind, P.A., MacIntyre, D.J., MacKinnon, D.F., Maier, R.M., Maier, W., Marchini, J., Mbarek, H., McGrath, P., McGuffin, P., Medland, S.E., Mehta, D., Middeldorp, C.M., Mihailov, E., Milaneschi, Y., Milani, L., Mondimore, F.M., Montgomery, G.W., Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R., O'Reilly, P.F., Oskarsson, H., Owen, M.J., Painter, J.N., Pedersen, C.B., Pedersen, M.G., Peterson, R.E., Pettersson, E., Peyrot, W.J., Pistis, G., Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P., Riley, B.P., Rivera, M., Mirza, S.S., Schoevers, R., Schulte, E.C., Shen, L., Shi, J.X., Shyn, S.I., Sigurdsson, E., Sinnamon, G.C.B., Smit, J.H., Smith, D.J., Stefansson, H., Steinberg, S., Strohmaier, J., Tansey, K.E., Teismann, H., Teumer, A., Thompson, W., Thomson, P.A., Thorgeirsson, T.E., Traylor, M., Trubetskoy, V., Uitterlinden, A.G., Umbricht, D., Auwera, S. van der, Hemert, A.M. van, Viktorin, A., Visscher, P.M., Wang, Y., Webb, B.T., Weinsheimer, S.M., Wellmann, J., Willemsen, G., Wu, Y., Xi, H.L.S., Yang, J., Zhang, F.T., Arolt, V., Berger, K., Boomsma, D.I., Cichon, S., Dannlowski, U., Geus, E.J.C. de, DePaulo, J.R., Domenici, E., Domschke, K., Esko, T., Grabe, H.J., Hamilton, S.P., Hayward, C., Heath, A.C., Kendler, K.S., Kloiber, S., Lewis, G., Li, Q.Q.S., Lucae, S., Madden, P.A.F., Magnusson, P.K., Martin, N.G., McIntosh, A.M., Metspalu, A., Mors, O., Mortensen, P.B., Muller-Myhsok, B., Nordentoft, M., O'Donovan, M.C., Paciga, S.A., Pedersen, N.L., Penninx, B.W.J.H., Perlis, R.H., Porteous, D.J., Potash, J.B., Preisig, M., Schaefer, C., Schulze, T.G., Smoller, J.W., Stefansson, K., Tiemeier, H., Uher, R., Voelzke, H., Weissman, M.M., Werge, T., Lewis, C.M., Levinson, D.F., Breen, G., Borglum, A.D., Sullivan, P.F., and Major Depressive Disorder Worki

Subjects
treatment-resistance, polygenic risk scores, depression, major depression, electroconvulsive therapy
Abstract

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistantdepression; disorder severity and unfavorable treatment outcomes are shown to be influencedby an increased genetic burden for major depression (MD). Here, we tested whether ECT assign-ment and response/nonresponse are associated with an increased genetic burden for majordepression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressiveepisode underwent ECT. MD-PRS were calculated for these inpatients and a separatepopulation-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on sum-mary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases:n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease statusbetween ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higherMD-PRS. MD-PRS in population-based depression self-reporters were intermediate betweenECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response(50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indi-cate that ECT cohorts show an increased genetic burden for MD and are consistent with thehypothesis that treatment-resistant MD patients represent a subgroup with an increased geneticrisk for MD. Larger samples are needed to better substantiate these findings.

Published
2019

36. Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations

Author

Cai, J., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Qian, H., Montgomery, C., Kelly, T.N., Cho, M.H., Weiss, S.T., Loos, R.J.F., Johnson, A.D., de Vries, P.S., Li, Y., Becker, L.C., Peralta, J.M., Wiggins, K.L., Bowden, D.W., Lasky-Su, J.A., Buyske, S., Shan, Y., Moon, J.-Y., Jorgenson, E., Cushman, M., Tiwari, H.K., Kooperberg, C., Faraday, N., Tapia, A.L., TOPMed Hematology & Hemostasis Working Group, Thornton, T.A., Choquet, H., Barnes, K.C., Bis, J.C., Hodonsky, C.J., Mathias, R.A., Wang, T., Taylor, K.D., He, J., Kaplan, R., Gupta, N., Lubitz, S.A., Smith, N.L., Daya, M., Rich, S.S., Peyser, P.A., Palmer, N.D., Silverman, E.K., Arnett, D.K., Choi, S.H., Cupples, L. A., Reiner, A.P., Argos, M., Boerwinkle, E., Hou, Z., Auer, P.L., Bien, S.A., Hidalgo, B., Ellinor, P.T., Heckbert, S.R., Gabriel, S., Tracy, R.P., Avery, C., Yanek, L.R., Raffield, L.M., Papanicolaou, G.J., Fornage, M., Z��llner, S., Graff, M., Wilson, J.G., Smith, J.A., Weng, L.-C., Morrison, A.C., Rosen, J.D., Irvin, M.R., North, K.E., Kardia, S.L.R., Pankratz, N., Rotter, J.I., Blangero, J., McHugh, C.P., Jain, D., Kowalski, M.H., and Ganesh, S.K.

Abstract

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count 86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

Published
2019
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37. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author

Hauser, M.A., Allingham, R.R., Aung, T., Heide, C.J. Van Der, Taylor, K.D., Rotter, J.I., Wang, S.J., Bonnemaijer, P.W.M., Williams, S.E., Abdullahi, S.M., Abu-Amero, K.K., Anderson, M.G., Akafo, S., Alhassan, M.B., Asimadu, I., Ayyagari, R., Bakayoko, S., Nyamsi, P.B., Bowden, D.W., Bromley, W.C., Budenz, D.L., Carmichael, T.R., Challa, P., Chen, Yi, Chuka-Okosa, C.M., Bailey, J.N., Costa, V.P., Cruz, Dario, DuBiner, H., Ervin, J.F., Feldman, R.M., Flamme-Wiese, M., Gaasterland, D.E., Garnai, S.J., Girkin, C.A., Guirou, N., Guo, X., Haines, J.L., Hammond, C.J., Herndon, L., Hoffmann, T.J., Hulette, C.M., Hydara, A., Igo, R.P., Jr., Jorgenson, E., Kabwe, J., Kilangalanga, N.J., Kizor-Akaraiwe, N., Kuchtey, R.W., Lamari, H., Li, Z, Liebmann, J.M., Liu, Y, Loos, R.J., Melo, M.B., Moroi, S.E., Msosa, J.M., Mullins, R.F., Nadkarni, G., Napo, A., Ng, M.C., Nunes, H.F., Obeng-Nyarkoh, E., Okeke, A., Okeke, S., Olaniyi, O., Olawoye, O., Oliveira, M.B., Pasquale, L.R., Perez-Grossmann, R.A., Pericak-Vance, M.A., Qin, X., Ramsay, M., Resnikoff, S., Richards, J.E., Schimiti, R.B., Sim, K.S., Sponsel, W.E., Svidnicki, P.V., Thiadens, A., Uche, N.J., Duijn, C.M. van, Vasconcellos, J.P.C. de, Wiggs, J.L., Zangwill, L.M., Risch, N., Milea, D., Ashaye, A., Klaver, C.C.W., Weinreb, R.N., Koch, A.E., Fingert, J.H., Khor, C.C., Hauser, M.A., Allingham, R.R., Aung, T., Heide, C.J. Van Der, Taylor, K.D., Rotter, J.I., Wang, S.J., Bonnemaijer, P.W.M., Williams, S.E., Abdullahi, S.M., Abu-Amero, K.K., Anderson, M.G., Akafo, S., Alhassan, M.B., Asimadu, I., Ayyagari, R., Bakayoko, S., Nyamsi, P.B., Bowden, D.W., Bromley, W.C., Budenz, D.L., Carmichael, T.R., Challa, P., Chen, Yi, Chuka-Okosa, C.M., Bailey, J.N., Costa, V.P., Cruz, Dario, DuBiner, H., Ervin, J.F., Feldman, R.M., Flamme-Wiese, M., Gaasterland, D.E., Garnai, S.J., Girkin, C.A., Guirou, N., Guo, X., Haines, J.L., Hammond, C.J., Herndon, L., Hoffmann, T.J., Hulette, C.M., Hydara, A., Igo, R.P., Jr., Jorgenson, E., Kabwe, J., Kilangalanga, N.J., Kizor-Akaraiwe, N., Kuchtey, R.W., Lamari, H., Li, Z, Liebmann, J.M., Liu, Y, Loos, R.J., Melo, M.B., Moroi, S.E., Msosa, J.M., Mullins, R.F., Nadkarni, G., Napo, A., Ng, M.C., Nunes, H.F., Obeng-Nyarkoh, E., Okeke, A., Okeke, S., Olaniyi, O., Olawoye, O., Oliveira, M.B., Pasquale, L.R., Perez-Grossmann, R.A., Pericak-Vance, M.A., Qin, X., Ramsay, M., Resnikoff, S., Richards, J.E., Schimiti, R.B., Sim, K.S., Sponsel, W.E., Svidnicki, P.V., Thiadens, A., Uche, N.J., Duijn, C.M. van, Vasconcellos, J.P.C. de, Wiggs, J.L., Zangwill, L.M., Risch, N., Milea, D., Ashaye, A., Klaver, C.C.W., Weinreb, R.N., Koch, A.E., Fingert, J.H., and Khor, C.C.

Abstract

Item does not contain fulltext, Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 x 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. Th

Published
2019

38. Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Author

Andlauer, T.F.M. (Till F. M.), Guzman-Parra, J. (Jose), Streit, F. (Fabian), Strohmaier, J. (Jana), González, M.J. (Maria José), Gil Flores, S. (Susana), Cabaleiro Fabeiro, F.J. (Francisco J.), del Río Noriega, F. (Francisco), Perez, F.P. (Fermin Perez), Haro González, J. (Jesus), Orozco Diaz, G. (Guillermo), Diego, Y. (Yolanda) de, Moreno-Küstner, B. (Berta), Auburger, G. (Georg), Degenhardt, F. (Franziska), Heilmann-Heimbach, S. (Stefanie), Herms, S. (Stefan), Hoffmann, P. (Per), Frank, J. (Josef), Foo, J.C. (Jerome C.), Treutlein, J. (Jens), Witt, S.H. (Stephanie H), Cichon, S. (Sven), Kogevinas, M. (Manolis), Stahl, E.A. (Eli A), Breen, G. (Gerome), Forstner, A.J. (Andreas J), McQuillin, A. (Andrew), Ripke, S. (Stephan), Trubetskoy, V. (Vassily), Mattheisen, M. (Manuel), Wang, Y. (Yunpeng), Coleman, J.R.I. (Jonathan R I), Gaspar, H.A. (Héléna A), Leeuw, C. (Christiaan) de, Steinberg, S. (Stacy), Pavlides, J.M.W. (Jennifer M Whitehead), Trzaskowski, M. (Maciej), Pers, T.H. (Tune H), Holmans, P.A. (Peter A.), Abbott, L. (Liam), Agerbo, E. (Esben), Akil, H. (Huda), Albani, D. (Diego), Alliey-Rodriguez, N. (Ney), Als, T.D. (Thomas D), Anjorin, A. (Adebayo), Antilla, V. (Verneri), Awasthi, S. (Swapnil), Badner, J.A. (Judith A), Bækvad-Hansen, M. (Marie), Barchas, J.D. (Jack D), Bass, N. (Nicholas), Bauer, M. (Michael), Belliveau, R.A. (Richard A.), Bergen, S.E. (Sarah), Pedersen, C.B. (C.), Bøen, E. (Erlend), Boks, M.P.M. (Marco), Boocock, J. (James), Budde, M. (Monika), Bunney, W.E. (William E), Burmeister, M., Bybjerg-Grauholm, J. (Jonas), Byerley, W.F. (William F), Casas, M. (Miquel), Cerrato, F. (Felecia), Cervantes, P. (Pablo), Chambert, K. (Kimberly), Charney, A.W. (Alexander W), Chen, D. (Danfeng), Churchhouse, C. (Claire), Clarke, T.-K. (Toni-Kim), Coryell, W.H. (William H), Craig, D.W. (David W), Cruceanu, C. (Cristiana), Czerski, P.M., Dale, A.M. (Anders), de Jong, S. (Simone), Del-Favero, J. (Jurgen), DePaulo, J.R. (J Raymond), Djurovic, S. (Srdjan), Dobbyn, A.L. (Amanda L), Dumont, A. (Ashley), Elvsåshagen, T. (Torbjørn), Escott-Price, V. (Valentina), Fan, C.C. (Chun Chieh), Fischer, S.B. (Sascha B), Flickinger, M. (Matthew), Foroud, T.M. (Tatiana M), Forty, L. (Liz), Fraser, C. (Christine), Luben, R.N. (Robert), Frisén, L. (Louise), Gade, K. (Katrin), Gage, D. (Diane), Garnham, J. (Julie), Giambartolomei, C. (Claudia), Pedersen, M.G. (Marianne Giørtz), Goldstein, J.I. (Jacqueline), Gordon, S.D. (Scott D), Gordon-Smith, K. (Katherine), Green, E.K. (Elaine K), Green, M.J. (Melissa J), Greenwood, T.A. (Tiffany A), Grove, J. (Jakob), Guan, W. (Weihua), Parra, J.G. (José Guzman), Hamshere, M.L. (Marian), Hautzinger, M. (Martin), Heilbronner, U. (Urs), Hipolito, M. (Maria), Holland, D. (Dominic), Huckins, L. (Laura), Jamain, S. (Stéphane), Johnson, J.S. (Jessica S), Juréus, A. (Anders), Kandaswamy, R. (Radhika), Karlsson, R. (Robert), Kennedy, J.L. (James L), Kittel-Schneider, S. (Sarah), Knowles, J.A. (James A), Koller, A.C. (Anna C), Kupka, R.W. (Ralph ), Lavebratt, C. (Catharina), Lawrence, J. (Jacob), Lawson, W.B. (William B), Leber, I. (Isabelle), Lee, P.H. (Phil H), Levy, S.E. (Shawn E), Li, J.Z. (Jun Z), Liu, C. (Chunyu), Lucae, S. (Susanne), Maaser, A. (Anna), Macintyre, D.J. (Donald J), Mahon, P.B. (Pamela B), Maier, W. (Wolfgang), Martinsson, L. (Lina), McCarroll, S.A. (Steve), McGuffin, P. (Peter), Mcinnis, M.G. (Melvin G), McKay, J.D. (James D), Medeiros, H. (Helena), Medland, S.E. (Sarah E), Meng, F. (Fan), Milani, L. (Lili), Montgomery, G.W. (Grant W), Morris, D.W. (Derek W), Mühleisen, T.W. (Thomas W), Mullins, N. (Niamh), Nguyen, H. (Hoang), Nievergelt, C.M. (Caroline M), Adolfsson, A.N. (Annelie Nordin), Nwulia, E.A. (Evaristus A), O’Donovan, C. (Claire), Loohuis, L.M.O. (Loes M Olde), Ori, A.P.S. (Anil P S), Oruc, L. (Lilijana), Ösby, U. (Urban), Perlis, R.H. (Roy H), Perry, A. (Amy), Pfennig, A. (Andrea), Potash, J.B. (James B), Purcell, S.M. (Shaun M), Regeer, E.J. (Eline Janet), Reif, A. (Andreas), Reinbold, C.S. (Céline S), Rice, J.P. (John), Richards, A. (Alex), Rivas, F. (Fabio), Rivera, M. (Margarita), Roussos, A. (Alexandra), Ruderfer, D. (Douglas), Ryu, J. (Julie), Sánchez-Mora, C. (Cristina), Schatzberg, A.F. (Alan F), Scheftner, W.A. (William A), Schork, N.J. (Nicholas), Weickert, C.S. (Cynthia Shannon), Shehktman, T. (Tatyana), Shilling, P.D. (Paul D), Sigurdsson, E. (Engilbert), Slaney, C. (Claire), Smeland, O.B. (Olav B), Sobell, J.L. (Janet L), Hansen, C.S. (Christine Søholm), Spijker, A.T. (Anne T), Clair, D.S., Steffens, M. (Michael), Strauss, J.S. (John S), Szelinger, S. (Szabolcs), Thompson, R.C. (Robert C), EThorgeirsson, T. (Thorgeir), Vedde, H. (Helmut), Wang, W. (Weiqing), Watson, S.J. (Stanley J), Weickert, T.W. (Thomas W), Xi, S. (Simon), Xu, W. (Wei), Young, A.H. (Allan H), Zandi, P.P. (Peter P), Zhang, P. (Ping), Zöllner, S. (Sebastian), Adolfsson, R., Agartz, I. (Ingrid), Alda, M. (Martin), Backlund, L. (Lena), Baune, B.T. (Bernhard T), Bellivier, F. (Frank), Berrettini, W. (Wade), Biernacka, J.M. (Joanna M), Blackwood, D.H.R. (Douglas), Boehnke, M. (Michael), Børglum, A.D. (Anders D), Corvin, A. (Aiden), Craddock, N. (Nicholas), Daly, M.J. (Mark), Dannlowski, U. (Udo), Esko, T. (Tõnu), Etain, B. (Bruno), Frye, M.A. (Mark A), Fullerton, J.M. (Janice M), Gershon, E.S. (Elliot S), Gill, M. (Michael), Goes, F. (Fernando), Grigoroiu-Serbanescu, M. (Maria), Hauser, J. (J.), Hougaard, D.M. (David M), Hultman, C.M. (Christina), Jones, I. (Ian), Jones, L.A. (Lisa A), Kahn, R. (René), Kirov, G. (George), Landén, M. (Mikael), Leboyer, M. (Marion), Lewis, C.M. (Cathryn), Li, Q.S. (Qingqin S), Lissowska, J. (Jolanta), Martin, N.G. (Nicholas), Mayoral, F. (Fermin), McElroy, S.L. (Susan L), McIntosh, A.M. (Andrew), Mcmahon, F.J. (Francis J), Melle, I. (Ingrid), Metspalu, A. (Andres), Mitchell, P.B. (Philip B), Morken, G. (Gunnar), Mors, O. (Ole), Mortensen, P.B. (Preben Bo), Müller-Myhsok, B. (Bertram), Myers, R.H. (Richard), Neale, B.M. (Benjamin), Nimgaonkar, V. (Vishwajit), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O’Donovan, M.C. (Michael C), Oedegaard, K.J. (Ketil J), Owen, M.J. (Michael J), Paciga, S.A. (Sara A), Pato, C. (Carlos), Posthuma, D. (Danielle), Ramos-Quiroga, J.A. (Josep Antoni), Ribasés, M. (Marta), Rietschel, M. (Marcella), Rouleau, G.A. (Guy A), Schalling, M. (Martin), Schofield, P.R. (Peter R), Schulze, T.G. (Thomas G), Serretti, A. (Alessandro), Smoller, J.W., Stefansson, H. (Hreinn), Zwart, J-A. (John-Anker), Stordal, E. (Eystein), Sullivan, P.F. (Patrick F), Turecki, G. (Gustavo), Vaaler, A.E. (Arne E), Vieta, E. (Eduard), Vincent, J.B. (John B), Werge, T.M. (Thomas), Nurnberger, J.I. (John I), Wray, N.R. (Naomi), Florio, A.D. (Arianna Di), Edenberg, H.J. (Howard), Ophoff, R.A. (Roel), Scott, L.J. (Laura J), Andreassen, O.A. (Ole), Kelsoe, J.R. (John), Sklar, P. (Pamela), Wray, N.R. (Naomi R), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J), Air, T.M. (Tracy M), Bacanu, S.A. (Silviu), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B), Binder, E.B. (Elisabeth), Bryois, J. (Julien), Buttenschøn, H.N. (Henriette N), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Colodro-Conde, L. (Lucía), Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E), Davies, G. (Gail), Deary, I.J. (Ian J), Degenhardt, F., Derks, E.M. (Eske M), Direk, N. (Nese), Dolan, C.V. (Conor), Dunn, E.C. (Erin C.), Eley, T.C. (T.), Kiadeh, F.F.H. (Farnush Farhadi Hassan), Finucane, H.K. (Hilary K), Foo, J.C. (Jerome C), Goes, F.S. (Fernando S), Gordon, S.D. (Scott D.), Hall, L.S. (Lynsey S), Hansen, T.F. (Thomas F), Hickie, I.B. (Ian), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David), Howard, D.M. (David M), Ising, M. (Marcus), Jansen, R. (Rick), Jones, I., Jones, L. (Louisa), Jorgenson, E. (Eric), Kohane, I.S. (Isaac S), Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Kutalik, Z. (Zoltán), Li, Y. (Yihan), Lind, P.A. (Penelope), MacIntyre, D.J. (Donald J), MacKinnon, D.F. (Dean F), Maier, R.M. (Robert M), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), Mcguffin, P. (Peter), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel M), Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Mondimore, F.M. (Francis M), Montgomery, G.W. (Grant), Mostafavi, S. (Sara), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O’Reilly, P.F. (Paul F), Oskarsson, H. (Hogni), Owen, M.J. (Michael), Painter, J.N. (Jodie N.), Pedersen, C.B. (Carsten Bøcker), Peterson, R.E. (Roseann E), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Quiroz, J.A. (Jorge A), Qvist, P. (Per), Rice, J.P. (John P), Riley, B.P. (Brien P.), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C), Shen, L. (Li), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Sinnamon, G.C.B. (Grant C B), Smith, A.V. (Davey), Smith, D.J. (Daniel J), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A), Thorgeirsson, T.E. (Thorgeir E), Traylor, M. (Matthew), Uitterlinden, A.G. (André), Umbricht, D. (Daniel), Van der Auwera, S. (Sandra), van Hemert, A.M. (Albert M), Viktorin, A. (Alexander), Visscher, P.M. (Peter M), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Wu, Y. (Yang), Xi, H.S. (Hualin S), Yang, J. (Joanna), Zhang, F. (Futao), Arolt, V. (Volker), Baune, B.T., Berger, K. (Klaus), Boomsma, D.I. (Dorret), Geus, E.J.C. (Eco) de, Domenici, E. (Enrico), Domschke, K. (Katharina), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Lewis, G., Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Martin, N.G. (Nicholas G), McIntosh, A.M. (Andrew M), Mors, O., Müller-Myhsok, B. (B.), Nöthen, M.M. (Markus M), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Porteous, D.J. (David J.), Preisig, M. (Martin), Schaefer, C. (Catherine), Smoller, J.W. (Jordan W), Stefansson, K. (Kari), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Völzke, H. (Henry), Weissman, M.M., Werge, T. (Thomas), Lewis, C.M. (Cathryn M), Levinson, D.F. (Douglas F.), Borglum, A.D. (Anders), Sullivan, P.F. (Patrick), Mayoral, F. (Fermín), Muller-Myhsok, B. (B.), Forstner, A.J. (Andreas J.), Nöthen, M.M. (Markus M.), Andlauer, T.F.M. (Till F. M.), Guzman-Parra, J. (Jose), Streit, F. (Fabian), Strohmaier, J. (Jana), González, M.J. (Maria José), Gil Flores, S. (Susana), Cabaleiro Fabeiro, F.J. (Francisco J.), del Río Noriega, F. (Francisco), Perez, F.P. (Fermin Perez), Haro González, J. (Jesus), Orozco Diaz, G. (Guillermo), Diego, Y. (Yolanda) de, Moreno-Küstner, B. (Berta), Auburger, G. (Georg), Degenhardt, F. 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(Claudia), Pedersen, M.G. (Marianne Giørtz), Goldstein, J.I. (Jacqueline), Gordon, S.D. (Scott D), Gordon-Smith, K. (Katherine), Green, E.K. (Elaine K), Green, M.J. (Melissa J), Greenwood, T.A. (Tiffany A), Grove, J. (Jakob), Guan, W. (Weihua), Parra, J.G. (José Guzman), Hamshere, M.L. (Marian), Hautzinger, M. (Martin), Heilbronner, U. (Urs), Hipolito, M. (Maria), Holland, D. (Dominic), Huckins, L. (Laura), Jamain, S. (Stéphane), Johnson, J.S. (Jessica S), Juréus, A. (Anders), Kandaswamy, R. (Radhika), Karlsson, R. (Robert), Kennedy, J.L. (James L), Kittel-Schneider, S. (Sarah), Knowles, J.A. (James A), Koller, A.C. (Anna C), Kupka, R.W. (Ralph ), Lavebratt, C. (Catharina), Lawrence, J. (Jacob), Lawson, W.B. (William B), Leber, I. (Isabelle), Lee, P.H. (Phil H), Levy, S.E. (Shawn E), Li, J.Z. (Jun Z), Liu, C. (Chunyu), Lucae, S. (Susanne), Maaser, A. (Anna), Macintyre, D.J. (Donald J), Mahon, P.B. (Pamela B), Maier, W. (Wolfgang), Martinsson, L. (Lina), McCarroll, S.A. 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(Thomas), Lewis, C.M. (Cathryn M), Levinson, D.F. (Douglas F.), Borglum, A.D. (Anders), Sullivan, P.F. (Patrick), Mayoral, F. (Fermín), Muller-Myhsok, B. (B.), Forstner, A.J. (Andreas J.), and Nöthen, M.M. (Markus M.)

Abstract

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Published
2019
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39. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author

Glanville, K.P. (Kylie P.), Coleman, J.R.I. (Jonathan R.I.), Hanscombe, K.B. (Ken B.), Euesden, J. (Jack), Choi, S.W. (Shing Wan), Purves, K.L. (Kirstin L.), Breen, G. (Gerome), Air, T.M. (Tracy M.), Andlauer, T.F.M. (Till F.M.), Baune, B.T., Binder, E.B. (Elisabeth), Blackwood, D.H.R. (Douglas), Boomsma, D.I. (Dorret), Buttenschøn, H.N. (Henriette N.), Colodro-Conde, L. (Lucía), Dannlowski, U. (Udo), Direk, N. (Nese), Dunn, E.C. (Erin C.), Forstner, A.J. (Andreas J.), Geus, E.J.C. (Eco) de, Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Jones, I., Jones, L. (Louisa), Knowles, J.A. (James A), Kutalik, Z. (Zoltán), Levinson, D.F. (Douglas F.), Lewis, G., Lind, P.A. (Penelope), Lucae, S. (Susanne), Magnusson, P.K. (Patrik), McGuffin, P. (Peter), McIntosh, A.M. (Andrew), Milaneschi, Y. (Yuri), Mors, O., Mostafavi, S. (Sara), Müller-Myhsok, B. (B.), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Potash, J.B. (James B), Preisig, M. (Martin), Ripke, S. (Stephan), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Smoller, J.W., Streit, F. (Fabian), Sullivan, P.F. (Patrick), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Van der Auwera, S. (Sandra), Weissman, M.M., Wray, N.R. (Naomi), Mattheisen, M. (Manuel), Trzaskowski, M. (Maciej), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J.), Agerbo, E. (Esben), Bacanu, S.A. (Silviu), Bækvad-Hansen, M. (Marie), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B.), Bryois, J. (Julien), Bybjerg-Grauholm, J. (Jonas), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E.), Davies, G. (Gail), Deary, I.J. (Ian J.), Degenhardt, F., Derks, E.M. (Eske), Dolan, C.V. (Conor), Eley, T.C. (T.), Escott-Price, V. (Valentina), Hassan Kiadeh, F.F. (Farnush Farhadi), Finucane, H.K. (Hilary K.), Foo, J.C. (Jerome C.), Frank, J. (Josef), Gaspar, H.A. (Héléna A.), Gill, M. (Michael), Goes, F.S. (Fernando S.), Gordon, S.D. (Scott D.), Grove, J. (Jakob), Hall, L.S. (Lynsey S.), Hansen, C.S. (Christine Søholm), Hansen, T.F. (Thomas F.), Herms, S. (Stefan), Hickie, I.B. (Ian), Hoffmann, P. (Per), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David), Howard, D.M. (David M.), Ising, M. (Marcus), Jansen, R. (Rick), Jorgenson, E. (Eric), Kohane, I.S. (Isaac S.), Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Li, Y. (Yihan), Macintyre, D.J. (Donald J), MacKinnon, D.F. (Dean F.), Maier, R.M. (Robert M.), Maier, W. (Wolfgang), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel), Mihailov, E. (Evelin), Milani, L. (Lili), Mondimore, F.M. (Francis M.), Montgomery, G.W. (Grant), Mullins, N. (Niamh), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O'Reilly, P.F. (Paul), Oskarsson, H. (Hogni), Owen, M.J. (Michael), Painter, J.N. (Jodie N.), Pedersen, C.B. (C.), Pedersen, M.G. (Marianne Giørtz), Peterson, R.E. (Roseann E.), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Posthuma, D. (Danielle), Quiroz, J.A. (Jorge A.), Qvist, P. (Per), Rice, J.P. (John), Riley, B.P. (Brien P.), Rivera, M. (Margarita), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C.), Shen, L. (Li), Sigurdsson, E. (Engilbert), Sinnamon, G.C.B. (Grant C.B.), Smith, A.V. (Davey), Smith, D.J. (Daniel J.), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Strohmaier, J. (Jana), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A.), Thorgeirsson, T.E. (Thorgeir E.), Traylor, M. (Matthew), Treutlein, J. (Jens), Trubetskoy, V. (Vassily), Uitterlinden, A.G. (Andrés G.), Umbricht, D. (Daniel), van Hemert, A.M. (Albert M.), Viktorin, A. (Alexander), Visscher, P.M. (Peter M.), Wang, Y. (Yunpeng), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Witt, S.H. (Stephanie H), Wu, Y. (Yang), Xi, H.S. (Hualin S.), Yang, J. (Jian), Zhang, F. (Futao), Arolt, V. (Volker), Berger, K. (Klaus), Cichon, S. (Sven), de Geus, E.J.C. (E. J.C.), DePaulo, J.R. (J. Raymond), Domenici, E. (Enrico), Domschke, K. (Katharina), Esko, T. (Tõnu), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Li, Q.S. (Qingqin S.), Madden, P.A. (Pamela), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Mortensen, P.B. (Preben Bo), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O'donovan, M.C. (Michael), Paciga, S.A. (Sara A.), Perlis, R.H. (Roy H), Porteous, D.J. (David J.), Rietschel, M. (Marcella), Schaefer, C. (Catherine), Schulze, T.G. (Thomas G.), Zwart, J-A. (John-Anker), Völzke, H. (Henry), Werge, T.M. (Thomas), Lewis, C.M. (Cathryn), Borglum, A.D. (Anders), Glanville, K.P. (Kylie P.), Coleman, J.R.I. (Jonathan R.I.), Hanscombe, K.B. (Ken B.), Euesden, J. (Jack), Choi, S.W. (Shing Wan), Purves, K.L. (Kirstin L.), Breen, G. (Gerome), Air, T.M. (Tracy M.), Andlauer, T.F.M. (Till F.M.), Baune, B.T., Binder, E.B. (Elisabeth), Blackwood, D.H.R. (Douglas), Boomsma, D.I. (Dorret), Buttenschøn, H.N. (Henriette N.), Colodro-Conde, L. (Lucía), Dannlowski, U. (Udo), Direk, N. (Nese), Dunn, E.C. (Erin C.), Forstner, A.J. (Andreas J.), Geus, E.J.C. (Eco) de, Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Jones, I., Jones, L. (Louisa), Knowles, J.A. (James A), Kutalik, Z. (Zoltán), Levinson, D.F. (Douglas F.), Lewis, G., Lind, P.A. (Penelope), Lucae, S. (Susanne), Magnusson, P.K. (Patrik), McGuffin, P. (Peter), McIntosh, A.M. (Andrew), Milaneschi, Y. (Yuri), Mors, O., Mostafavi, S. (Sara), Müller-Myhsok, B. (B.), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Potash, J.B. (James B), Preisig, M. (Martin), Ripke, S. (Stephan), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Smoller, J.W., Streit, F. (Fabian), Sullivan, P.F. (Patrick), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Van der Auwera, S. (Sandra), Weissman, M.M., Wray, N.R. (Naomi), Mattheisen, M. (Manuel), Trzaskowski, M. (Maciej), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J.), Agerbo, E. (Esben), Bacanu, S.A. (Silviu), Bækvad-Hansen, M. (Marie), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B.), Bryois, J. (Julien), Bybjerg-Grauholm, J. (Jonas), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E.), Davies, G. (Gail), Deary, I.J. (Ian J.), Degenhardt, F., Derks, E.M. (Eske), Dolan, C.V. (Conor), Eley, T.C. (T.), Escott-Price, V. (Valentina), Hassan Kiadeh, F.F. (Farnush Farhadi), Finucane, H.K. (Hilary K.), Foo, J.C. (Jerome C.), Frank, J. (Josef), Gaspar, H.A. (Héléna A.), Gill, M. (Michael), Goes, F.S. (Fernando S.), Gordon, S.D. (Scott D.), Grove, J. (Jakob), Hall, L.S. (Lynsey S.), Hansen, C.S. (Christine Søholm), Hansen, T.F. (Thomas F.), Herms, S. (Stefan), Hickie, I.B. (Ian), Hoffmann, P. (Per), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David), Howard, D.M. (David M.), Ising, M. (Marcus), Jansen, R. (Rick), Jorgenson, E. (Eric), Kohane, I.S. (Isaac S.), Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Li, Y. (Yihan), Macintyre, D.J. (Donald J), MacKinnon, D.F. (Dean F.), Maier, R.M. (Robert M.), Maier, W. (Wolfgang), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel), Mihailov, E. (Evelin), Milani, L. (Lili), Mondimore, F.M. (Francis M.), Montgomery, G.W. (Grant), Mullins, N. (Niamh), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O'Reilly, P.F. (Paul), Oskarsson, H. (Hogni), Owen, M.J. (Michael), Painter, J.N. (Jodie N.), Pedersen, C.B. (C.), Pedersen, M.G. (Marianne Giørtz), Peterson, R.E. (Roseann E.), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Posthuma, D. (Danielle), Quiroz, J.A. (Jorge A.), Qvist, P. (Per), Rice, J.P. (John), Riley, B.P. (Brien P.), Rivera, M. (Margarita), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C.), Shen, L. (Li), Sigurdsson, E. (Engilbert), Sinnamon, G.C.B. (Grant C.B.), Smith, A.V. (Davey), Smith, D.J. (Daniel J.), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Strohmaier, J. (Jana), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A.), Thorgeirsson, T.E. (Thorgeir E.), Traylor, M. (Matthew), Treutlein, J. (Jens), Trubetskoy, V. (Vassily), Uitterlinden, A.G. (Andrés G.), Umbricht, D. (Daniel), van Hemert, A.M. (Albert M.), Viktorin, A. (Alexander), Visscher, P.M. (Peter M.), Wang, Y. (Yunpeng), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Witt, S.H. (Stephanie H), Wu, Y. (Yang), Xi, H.S. (Hualin S.), Yang, J. (Jian), Zhang, F. (Futao), Arolt, V. (Volker), Berger, K. (Klaus), Cichon, S. (Sven), de Geus, E.J.C. (E. J.C.), DePaulo, J.R. (J. Raymond), Domenici, E. (Enrico), Domschke, K. (Katharina), Esko, T. (Tõnu), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Li, Q.S. (Qingqin S.), Madden, P.A. (Pamela), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Mortensen, P.B. (Preben Bo), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O'donovan, M.C. (Michael), Paciga, S.A. (Sara A.), Perlis, R.H. (Roy H), Porteous, D.J. (David J.), Rietschel, M. (Marcella), Schaefer, C. (Catherine), Schulze, T.G. (Thomas G.), Zwart, J-A. (John-Anker), Völzke, H. (Henry), Werge, T.M. (Thomas), Lewis, C.M. (Cathryn), and Borglum, A.D. (Anders)

Abstract

Background: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. Methods: We fine-mapped the classical MHC (chr6: 29.6–33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10−6) and a candidate threshold (1.6 × 10−4). Results: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97–0.99). Conclusions: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Published
2019
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40. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Author

Czamara, D. (Darina), Eraslan, G. (Gökçen), Page, C.M. (Christian M.), Lahti, J. (Jari), Lahti-Pulkkinen, M. (Marius), Hämäläinen, E. (Esa), Kajantie, E. (Eero), Laivuori, H. (Hannele), Villa, P.M. (Pia M.), Reynolds, R.M. (Rebecca M.), Nystad, W. (Wenche), Håberg, S.E. (Siri E), London, S.J. (Stephanie J.), O’Donnell, K.J. (Kieran J.), Garg, E. (Elika), Meaney, M.J., Entringer, S., Wadhwa, P.D. (Pathik D.), Buss, C. (Claudia), Jones, M.J. (Meaghan J.), Lin, D.T.S. (David T. S.), MacIsaac, J.L. (Julie L.), Kobor, M.S. (Michael S.), Koen, N. (Nastassja), Zar, H.J., Koenen, M.E. (Marjorie), Dalvie, S. (Shareefa), Stein, D.J. (Dan), Kondofersky, I. (Ivan), Müller, N.S. (Nikola S.), Theis, F. (Fabian), Wray, N.R. (Naomi), Ripke, S. (Stephan), Mattheisen, M. (Manuel), Trzaskowski, M. (Maciej), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J.), Agerbo, E. (Esben), Air, T.M. (Tracy M.), Andlauer, T.F.M. (Till F. M.), Bacanu, S.A. (Silviu), Bækvad-Hansen, M. (Marie), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B.), Blackwood, D.H.R. (Douglas), Bryois, J. (Julien), Buttenschøn, H.N. (Henriette N.), Bybjerg-Grauholm, J. (Jonas), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Coleman, J.R.I. (Jonathan R. I.), Colodro-Conde, L. (Lucía), Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E.), Davies, G. (Gail), Deary, I.J. (Ian), Degenhardt, F., Derks, E.M. (Eske), Direk, N. (Nese), Dolan, C.V. (Conor), Dunn, E.C. (Erin C.), Eley, T.C. (T.), Escott-Price, V. (Valentina), Kiadeh, F.F.H. (Farnush Farhadi Hassan), Finucane, H.K. (Hilary K.), Forstner, A.J. (Andreas J.), Frank, J. (Josef), Gaspar, H.A. (Héléna A.), Gill, M. (Michael), Goes, F.S. (Fernando S.), Gordon, S.D. (Scott D.), Grove, J. (Jakob), Hall, L.S. (Lynsey S.), Hansen, C.S. (Christine Søholm), Hansen, T.F. (Thomas F.), Herms, S. (Stefan), Hickie, I.B. (Ian), Hoffmann, P. (Per), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David M.), Ising, M. (Marcus), Jansen, R. (Rick), Jorgenson, E. (Eric), Knowles, J.A. (James A), Kohane, I.S., Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Krogh, J. (Jesper), Kutalik, Z. (Zoltán), Li, Y. (Yihan), Lind, P.A. (Penelope), Macintyre, D.J. (Donald J), MacKinnon, D.F. (Dean F.), Maier, R.M. (Robert M.), Maier, W. (Wolfgang), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), McGuffin, P. (Peter), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel), Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mondimore, F.M. (Francis M.), Montgomery, G.W. (Grant), Mostafavi, S. (Sara), Mullins, N. (Niamh), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O’Reilly, P.F. (Paul F.), Oskarsson, H. (Hogni), Owen, M.J. (Michael J.), Painter, J.N. (Jodie N.), Pedersen, C.B. (C.), Pedersen, M.G. (Marianne Giørtz), Peterson, R.E. (Roseann E.), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Posthuma, D. (Danielle), Quiroz, J.A. (Jorge A.), Qvist, P. (Per), Rice, J.P. (John), Riley, B.P. (Brien P.), Rivera, M. (Margarita), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C.), Shen, L. (Ling), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Sigurdsson, E. (Engilbert), Sinnamon, G.C.B. (Grant C. B.), Smith, A.V. (Davey), Smith, D.J. (Daniel J.), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Streit, F. (Fabian), Strohmaier, J. (Jana), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A.), Thorgeirsson, T.E. (Thorgeir E.), Traylor, M. (Matthew), Treutlein, J. (Jens), Trubetskoy, V. (Vassily), Uitterlinden, A.G. (André), Umbricht, D. (Daniel), Van der Auwera, S. (Sandra), van Hemert, A.M. (Albert M.), Viktorin, A. (Alexander), Visscher, P.M. (Peter M.), Wang, Y. (Yunpeng), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Witt, S.H. (Stephanie H), Wu, Y. (Yang), Xi, H.S. (Hualin S.), Yang, J. (Jian), Zhang, F. (Futao), Arolt, V. (Volker), Baune, B.T., Berger, K. (Klaus), Boomsma, D.I. (Dorret), Cichon, S. (Sven), Dannlowski, U. (Udo), Geus, E.J.C. (Eco) de, DePaulo, J.R. (J. Raymond), Domenici, E. (Enrico), Domschke, K. (Katharina), Esko, T. (Tõnu), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Lewis, G., Li, Q.S. (Qingqin S.), Lucae, S. (Susanne), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik K.), Martin, N.G. (Nicholas), McIntosh, A.M. (Andrew M.), Metspalu, A. (Andres), Mors, O. (Ole), Mortensen, P.B. (Preben Bo), Müller-Myhsok, B. (B.), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O’Donovan, M.C. (Michael C.), Paciga, S.A. (Sara A.), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Perlis, R.H. (Roy H), Porteous, D.J. (David J.), Potash, J.B. (James B), Preisig, M. (Martin), Rietschel, M. (Marcella), Schaefer, C. (Catherine), Schulze, T.G. (Thomas G.), Smoller, J.W., Stefansson, K. (Kari), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Völzke, H. (Henry), Weissman, M.M., Werge, T. (Thomas), Lewis, C.M. (Cathryn), Levinson, D.F. (Douglas F.), Breen, G. (Gerome), Borglum, A.D. (Anders), Sullivan, P.F. (Patrick F.), Räikkönen, K. (Katri), Binder, E.B. (Elisabeth), Czamara, D. (Darina), Eraslan, G. (Gökçen), Page, C.M. (Christian M.), Lahti, J. (Jari), Lahti-Pulkkinen, M. (Marius), Hämäläinen, E. (Esa), Kajantie, E. (Eero), Laivuori, H. (Hannele), Villa, P.M. (Pia M.), Reynolds, R.M. (Rebecca M.), Nystad, W. (Wenche), Håberg, S.E. (Siri E), London, S.J. (Stephanie J.), O’Donnell, K.J. (Kieran J.), Garg, E. (Elika), Meaney, M.J., Entringer, S., Wadhwa, P.D. (Pathik D.), Buss, C. (Claudia), Jones, M.J. (Meaghan J.), Lin, D.T.S. (David T. S.), MacIsaac, J.L. (Julie L.), Kobor, M.S. (Michael S.), Koen, N. (Nastassja), Zar, H.J., Koenen, M.E. (Marjorie), Dalvie, S. (Shareefa), Stein, D.J. (Dan), Kondofersky, I. (Ivan), Müller, N.S. (Nikola S.), Theis, F. (Fabian), Wray, N.R. (Naomi), Ripke, S. (Stephan), Mattheisen, M. (Manuel), Trzaskowski, M. (Maciej), Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Adams, M.J. (Mark J.), Agerbo, E. (Esben), Air, T.M. (Tracy M.), Andlauer, T.F.M. (Till F. M.), Bacanu, S.A. (Silviu), Bækvad-Hansen, M. (Marie), Beekman, A.T.F. (Aartjan), Bigdeli, T.B. (Tim B.), Blackwood, D.H.R. (Douglas), Bryois, J. (Julien), Buttenschøn, H.N. (Henriette N.), Bybjerg-Grauholm, J. (Jonas), Cai, N. (Na), Castelao, E. (Enrique), Christensen, J.H. (Jane Hvarregaard), Clarke, T.-K., Coleman, J.R.I. (Jonathan R. I.), Colodro-Conde, L. (Lucía), Couvy-Duchesne, B. (Baptiste), Craddock, N.J. (Nick), Crawford, G.E. (Gregory E.), Davies, G. (Gail), Deary, I.J. (Ian), Degenhardt, F., Derks, E.M. (Eske), Direk, N. (Nese), Dolan, C.V. (Conor), Dunn, E.C. (Erin C.), Eley, T.C. (T.), Escott-Price, V. (Valentina), Kiadeh, F.F.H. (Farnush Farhadi Hassan), Finucane, H.K. (Hilary K.), Forstner, A.J. (Andreas J.), Frank, J. (Josef), Gaspar, H.A. (Héléna A.), Gill, M. (Michael), Goes, F.S. (Fernando S.), Gordon, S.D. (Scott D.), Grove, J. (Jakob), Hall, L.S. (Lynsey S.), Hansen, C.S. (Christine Søholm), Hansen, T.F. (Thomas F.), Herms, S. (Stefan), Hickie, I.B. (Ian), Hoffmann, P. (Per), Homuth, G. (Georg), Horn, C. (Carsten), Hottenga, J.J. (Jouke Jan), Hougaard, D.M. (David M.), Ising, M. (Marcus), Jansen, R. (Rick), Jorgenson, E. (Eric), Knowles, J.A. (James A), Kohane, I.S., Kraft, J. (Julia), Kretzschmar, W.W. (Warren W.), Krogh, J. (Jesper), Kutalik, Z. (Zoltán), Li, Y. (Yihan), Lind, P.A. (Penelope), Macintyre, D.J. (Donald J), MacKinnon, D.F. (Dean F.), Maier, R.M. (Robert M.), Maier, W. (Wolfgang), Marchini, J. (Jonathan), Mbarek, H., McGrath, P. (Patrick), McGuffin, P. (Peter), Medland, S.E. (Sarah), Mehta, D. (Divya), Middeldorp, C.M. (Christel), Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mondimore, F.M. (Francis M.), Montgomery, G.W. (Grant), Mostafavi, S. (Sara), Mullins, N. (Niamh), Nauck, M. (Matthias), Ng, B. (Bernard), Nivard, M. (Michel), Nyholt, D.R. (Dale), O’Reilly, P.F. (Paul F.), Oskarsson, H. (Hogni), Owen, M.J. (Michael J.), Painter, J.N. (Jodie N.), Pedersen, C.B. (C.), Pedersen, M.G. (Marianne Giørtz), Peterson, R.E. (Roseann E.), Pettersson, E. (Erik), Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Posthuma, D. (Danielle), Quiroz, J.A. (Jorge A.), Qvist, P. (Per), Rice, J.P. (John), Riley, B.P. (Brien P.), Rivera, M. (Margarita), Mirza, S.S. (Saira), Schoevers, R. (Robert), Schulte, E.C. (Eva C.), Shen, L. (Ling), Shi, J. (Jianxin), Shyn, S.I. (Stanley I), Sigurdsson, E. (Engilbert), Sinnamon, G.C.B. (Grant C. B.), Smith, A.V. (Davey), Smith, D.J. (Daniel J.), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Streit, F. (Fabian), Strohmaier, J. (Jana), Tansey, K.E., Teismann, H. (Henning), Teumer, A. (Alexander), Thompson, W.K. (Wesley K.), Thomson, P.A. (Pippa A.), Thorgeirsson, T.E. (Thorgeir E.), Traylor, M. (Matthew), Treutlein, J. (Jens), Trubetskoy, V. (Vassily), Uitterlinden, A.G. (André), Umbricht, D. (Daniel), Van der Auwera, S. (Sandra), van Hemert, A.M. (Albert M.), Viktorin, A. (Alexander), Visscher, P.M. (Peter M.), Wang, Y. (Yunpeng), Webb, B.T. (Bradley T.), Weinsheimer, S.M. (Shantel Marie), Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Witt, S.H. (Stephanie H), Wu, Y. (Yang), Xi, H.S. (Hualin S.), Yang, J. (Jian), Zhang, F. (Futao), Arolt, V. (Volker), Baune, B.T., Berger, K. (Klaus), Boomsma, D.I. (Dorret), Cichon, S. (Sven), Dannlowski, U. (Udo), Geus, E.J.C. (Eco) de, DePaulo, J.R. (J. Raymond), Domenici, E. (Enrico), Domschke, K. (Katharina), Esko, T. (Tõnu), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Hayward, C. (Caroline), Heath, A.C. (Andrew), Jablensky, A. (Assen), Kloiber, S. (Stefan), Lewis, G., Li, Q.S. (Qingqin S.), Lucae, S. (Susanne), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik K.), Martin, N.G. (Nicholas), McIntosh, A.M. (Andrew M.), Metspalu, A. (Andres), Mors, O. (Ole), Mortensen, P.B. (Preben Bo), Müller-Myhsok, B. (B.), Nordentoft, M. (Merete), Nöthen, M.M. (Markus), O’Donovan, M.C. (Michael C.), Paciga, S.A. (Sara A.), Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Perlis, R.H. (Roy H), Porteous, D.J. (David J.), Potash, J.B. (James B), Preisig, M. (Martin), Rietschel, M. (Marcella), Schaefer, C. (Catherine), Schulze, T.G. (Thomas G.), Smoller, J.W., Stefansson, K. (Kari), Tiemeier, H.W. (Henning), Uher, R. (Rudolf), Völzke, H. (Henry), Weissman, M.M., Werge, T. (Thomas), Lewis, C.M. (Cathryn), Levinson, D.F. (Douglas F.), Breen, G. (Gerome), Borglum, A.D. (Anders), Sullivan, P.F. (Patrick F.), Räikkönen, K. (Katri), and Binder, E.B. (Elisabeth)

Abstract

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

Published
2019
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41. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Author

Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF

Abstract

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression; disorder severity and unfavorable treatment outcomes are shown to be influenced by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment and response/nonresponse are associated with an increased genetic burden for major depression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive episode underwent ECT. MD-PRS were calculated for these inpatients and a separate population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases: n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate that ECT cohorts show an increased genetic burden for MD and are consistent with the hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic risk for MD. Larger samples are needed to better substantiate these findings.

Published
2019

42. Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Author

Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, Sullivan, PF, Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, and Sullivan, PF

Abstract

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

Published
2019

43. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Author

Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF

Abstract

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

Published
2019

45. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis

Author

Dahlin, A., Lu, Q., Himes, B.E., Randell, S.H., Israel, E., Kan, M., Weiss, S.T., Sun, M., Wu, A.C., Tantisira, K., Panganiban, R.A., Shore, S., Iribarren, C., Park, H.-R., Park, J.-A., Jorgenson, E., and Mitchel, J.A.

Abstract

Background: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. Objectives: We sought to identify and characterize functional variants in the 17q21 locus. Methods: We used the Exome Aggregation Consortium browser to identify coding (amino acid–changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants. Results: Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10−6) and EVE (odds ratio, 0.85; joint PEVE = 1.31 × 10−13). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein. Conclusions: Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.

Published
2018
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46. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author

de Jong, S, Diniz, MJA, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, SA, Bækvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, JJ, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, de Jong, S, Diniz, MJA, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, SA, Bækvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, JJ, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, and Painter, JN

Abstract

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

Published
2018

47. Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Author

Arnau-Soler, A., Adams, M. J., Hayward, C. (Caroline), Thomson, PA, Porteous, D, Campbell, A. (Archie), Smith, B.H. (Blair), Black, C., Padmanabhan, S. (Sandosh), Mcintosh, A.M. (Andrew), Wray, N.R. (Naomi), Ripke, S. (Stephan), Mattheisen, M. (Manuel), Trzaskowski, M., Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Agerbo, E, Air, T.M., Andlauer, T.F.M., Bacanu, SA, Bækvad-Hansen, M., Beekman, A.T.F. (Aartjan), Bigdeli, TB, Binder, E.B. (Elisabeth), Blackwood, D.H.R. (Douglas), Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E, Christensen, J.H., Clarke, T.-K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N.J. (Nick), Crawford, G.E., Davies, G. (Gail), Deary, I.J. (Ian), Degenhardt, F., Derks, E.M. (Eske), Direk, N., Dolan, C.V. (Conor), Dunn, EC, Eley, T.C. (T.), Escott-Price, V, Kiadeh, F.F.H., Finucane, HK, Forstner, A.J. (Andreas), Frank, J. (Josef), Gaspar, H.A., Gill, M. (Michael), Goes, F.S., Gordon, S.D., Grove, J. (Jakob), Hall, L.S., Hansen, C.S., Hansen, T.F. (Thomas F), Herms, S. (Stefan), Hickie, I.B. (Ian), Hoffmann, P. (Per), Homuth, G. (Georg), Horn, C., Hottenga, JJ, Hougaard, D.M. (David), Ising, M. (Marcus), Jansen, R, Jorgenson, E, Knowles, J.A. (James A), Kohane, IS, Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z. (Zoltán), Li, Y. (Yuwen), Lind, P.A. (Penelope), Macintyre, D.J. (Donald J), MacKinnon, D.F., Maier, R.M., Maier, W. (Wolfgang), Marchini, J. (Jonathan), Mbarek, H, McGrath, P., Mcguffin, P. (Peter), Medland, S.E., Mehta, D, Middeldorp, CM, Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mondimore, F.M., Montgomery, G.W. (Grant), Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R. (Dale), O'Reilly, P.F. (Paul), Oskarsson, H. (Hogni), Owen, M.J., Painter, JN, Pedersen, CB, Pedersen, M.G., Peterson, R.E., Pettersson, E, Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P. (John), Riley, B.P. (Brien), Rivera, M., Mirza, S.S., Schoevers, R. (Robert), Schulte, E.C., Shen, L. (Li), Shi, J. (Julia), Shyn, S.I. (Stanley I), Sigurdsson, E. (Engilbert), Sinnamon, G.C.B., Smit, J.H.M., Smith, D.J. (Derek James), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Streit, F., Strohmaier, J., Tansey, KE, Teismann, H., Teumer, A. (Alexander), Thompson, W., Thorgeirsson, T.E. (Thorgeir), Traylor, M. (Matthew), Treutlein, J. (Jens), Trubetskoy, V., Uitterlinden, A.G. (André), Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A, Visscher, P.M. (Peter), Wang, Y. (Yijing), Webb, BT, Weinsheimer, S.M., Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Witt, S.H. (Stephanie H), Wu, Y., Xi, HS, Yang, J., Zhang, F. (Feng), Arolt, V, Baune, BT, Berger, K. (Klaus), Boomsma, D.I. (Dorret), Cichon, S. (Sven), Dannlowski, U., de Geus, EJCN, DePaulo, J.R., Domenici, E, Domschke, K., Esko, T. (Tõnu), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Heath, A.C. (Andrew), Kendler, K. (K.), Kloiber, S, Lewis, G, Li, Q.S., Lucae, S. (Susanne), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Martin, N.G. (Nicholas), Metspalu, A. (Andres), Mors, O., Mortensen, P.B., Müller-Myhsok, B., Nordentoft, M, Nöthen, M.M. (Markus), O'Donovan, M. (Michael), Paciga, S.A., Pedersen, N.L. (Nancy), Penninx, B.W.J.H. (Brenda), Perlis, R.H. (Roy H), Porteous, D.J. (David J.), Potash, J.B. (James B), Preisig, M. (Martin), Rietschel, M., Schaefer, C. (Catherine), Schulze, T.G. (Thomas), Smoller, J.W., Zwart, J-A. (John-Anker), Tiemeier, H.W. (Henning), Uher, R, Völzke, H. (Henry), Weissman, M.M. (Myrna M), Werge, T.M. (Thomas), Lewis, C.M. (Cathryn), Levinson, D.F. (Douglas), Breen, G. (Gerome), Børglum, A.D., Sullivan, P.F. (Patrick), Arnau-Soler, A., Adams, M. J., Hayward, C. (Caroline), Thomson, PA, Porteous, D, Campbell, A. (Archie), Smith, B.H. (Blair), Black, C., Padmanabhan, S. (Sandosh), Mcintosh, A.M. (Andrew), Wray, N.R. (Naomi), Ripke, S. (Stephan), Mattheisen, M. (Manuel), Trzaskowski, M., Byrne, E.M. (Enda), Abdellaoui, A. (Abdel), Agerbo, E, Air, T.M., Andlauer, T.F.M., Bacanu, SA, Bækvad-Hansen, M., Beekman, A.T.F. (Aartjan), Bigdeli, TB, Binder, E.B. (Elisabeth), Blackwood, D.H.R. (Douglas), Bryois, J., Buttenschøn, H.N., Bybjerg-Grauholm, J., Cai, N., Castelao, E, Christensen, J.H., Clarke, T.-K., Coleman, J.R.I., Colodro-Conde, L., Couvy-Duchesne, B., Craddock, N.J. (Nick), Crawford, G.E., Davies, G. (Gail), Deary, I.J. (Ian), Degenhardt, F., Derks, E.M. (Eske), Direk, N., Dolan, C.V. (Conor), Dunn, EC, Eley, T.C. (T.), Escott-Price, V, Kiadeh, F.F.H., Finucane, HK, Forstner, A.J. (Andreas), Frank, J. (Josef), Gaspar, H.A., Gill, M. (Michael), Goes, F.S., Gordon, S.D., Grove, J. (Jakob), Hall, L.S., Hansen, C.S., Hansen, T.F. (Thomas F), Herms, S. (Stefan), Hickie, I.B. (Ian), Hoffmann, P. (Per), Homuth, G. (Georg), Horn, C., Hottenga, JJ, Hougaard, D.M. (David), Ising, M. (Marcus), Jansen, R, Jorgenson, E, Knowles, J.A. (James A), Kohane, IS, Kraft, J., Kretzschmar, W.W., Krogh, J., Kutalik, Z. (Zoltán), Li, Y. (Yuwen), Lind, P.A. (Penelope), Macintyre, D.J. (Donald J), MacKinnon, D.F., Maier, R.M., Maier, W. (Wolfgang), Marchini, J. (Jonathan), Mbarek, H, McGrath, P., Mcguffin, P. (Peter), Medland, S.E., Mehta, D, Middeldorp, CM, Mihailov, E. (Evelin), Milaneschi, Y. (Yuri), Milani, L. (Lili), Mondimore, F.M., Montgomery, G.W. (Grant), Mostafavi, S., Mullins, N., Nauck, M., Ng, B., Nivard, M.G., Nyholt, D.R. (Dale), O'Reilly, P.F. (Paul), Oskarsson, H. (Hogni), Owen, M.J., Painter, JN, Pedersen, CB, Pedersen, M.G., Peterson, R.E., Pettersson, E, Peyrot, W.J. (Wouter ), Pistis, G. (Giorgio), Posthuma, D., Quiroz, J.A., Qvist, P., Rice, J.P. (John), Riley, B.P. (Brien), Rivera, M., Mirza, S.S., Schoevers, R. (Robert), Schulte, E.C., Shen, L. (Li), Shi, J. (Julia), Shyn, S.I. (Stanley I), Sigurdsson, E. (Engilbert), Sinnamon, G.C.B., Smit, J.H.M., Smith, D.J. (Derek James), Stefansson, H. (Hreinn), Steinberg, S. (Stacy), Streit, F., Strohmaier, J., Tansey, KE, Teismann, H., Teumer, A. (Alexander), Thompson, W., Thorgeirsson, T.E. (Thorgeir), Traylor, M. (Matthew), Treutlein, J. (Jens), Trubetskoy, V., Uitterlinden, A.G. (André), Umbricht, D., Van der Auwera, S., van Hemert, A.M., Viktorin, A, Visscher, P.M. (Peter), Wang, Y. (Yijing), Webb, BT, Weinsheimer, S.M., Wellmann, J. (Jürgen), Willemsen, G.A.H.M. (Gonneke), Witt, S.H. (Stephanie H), Wu, Y., Xi, HS, Yang, J., Zhang, F. (Feng), Arolt, V, Baune, BT, Berger, K. (Klaus), Boomsma, D.I. (Dorret), Cichon, S. (Sven), Dannlowski, U., de Geus, EJCN, DePaulo, J.R., Domenici, E, Domschke, K., Esko, T. (Tõnu), Grabe, H.J. (Hans Jörgen), Hamilton, S.P. (Steven P), Heath, A.C. (Andrew), Kendler, K. (K.), Kloiber, S, Lewis, G, Li, Q.S., Lucae, S. (Susanne), Madden, P.A. (Pamela), Magnusson, P.K. (Patrik), Martin, N.G. 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Abstract

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of d

Published
2018
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