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1. Genome-wide association study of Tourettes syndrome.

Author

Neale, B, Stewart, S, Fagerness, J, Evans, P, Gamazon, E, Edlund, C, Service, S, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, L, Han, B, Crane, J, Scharf, J, Yu, D, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, D, Smit, J, King, R, Fernandez, T, Leckman, J, Kidd, K, Kidd, J, Pakstis, A, Herrera, L, Romero, R, Fournier, E, Sandor, P, Barr, C, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, C, Bruun, R, Erenberg, G, Naarden, A, Lee, P, Weiss, N, Kremeyer, B, Berrío, G, Campbell, D, Cardona Silgado, J, Ochoa, W, Mesa Restrepo, S, Muller, H, Valencia Duarte, A, Lyon, G, Leppert, M, Morgan, J, Weiss, R, Grados, M, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, J, Heiman, G, Gilbert, D, Hoekstra, P, Robertson, M, Kurlan, R, Liu, C, Gibbs, J, Singleton, A, Hardy, J, Strengman, E, Crenshaw, A, Parkin, M, Wagner, M, Moessner, R, Mirel, D, Posthuma, D, Sabatti, C, Conti, D, Knowles, J, Ruiz-Linares, A, Rouleau, G, Purcell, S, Heutink, P, Oostra, B, McMahon, W, Cox, N, Pauls, D, Reus, Victor, State, Matthew, Eskin, Eleazar, Mathews, Carol, Lowe, Thomas, Freimer, Nelson, Ophoff, Roel, and Moorjani, Priya

Subjects
Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Chromosomes, Human, Pair 9, Female, Fibrillar Collagens, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, International Cooperation, Male, Meta-Analysis as Topic, Obsessive-Compulsive Disorder, Polymorphism, Single Nucleotide, Tourette Syndrome, White People, Young Adult
Abstract

Tourettes syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Published
2013

2. Genome-wide association study of Tourette's syndrome.

Author

Scharf, JM, Yu, D, Mathews, CA, Neale, BM, Stewart, SE, Fagerness, JA, Evans, P, Gamazon, E, Edlund, CK, Service, SK, Tikhomirov, A, Osiecki, L, Illmann, C, Pluzhnikov, A, Konkashbaev, A, Davis, LK, Han, B, Crane, J, Moorjani, P, Crenshaw, AT, Parkin, MA, Reus, VI, Lowe, TL, Rangel-Lugo, M, Chouinard, S, Dion, Y, Girard, S, Cath, DC, Smit, JH, King, RA, Fernandez, TV, Leckman, JF, Kidd, KK, Kidd, JR, Pakstis, AJ, State, MW, Herrera, LD, Romero, R, Fournier, E, Sandor, P, Barr, CL, Phan, N, Gross-Tsur, V, Benarroch, F, Pollak, Y, Budman, CL, Bruun, RD, Erenberg, G, Naarden, AL, Lee, PC, Weiss, N, Kremeyer, B, Berrío, GB, Campbell, DD, Cardona Silgado, JC, Ochoa, WC, Mesa Restrepo, SC, Muller, H, Valencia Duarte, AV, Lyon, GJ, Leppert, M, Morgan, J, Weiss, R, Grados, MA, Anderson, K, Davarya, S, Singer, H, Walkup, J, Jankovic, J, Tischfield, JA, Heiman, GA, Gilbert, DL, Hoekstra, PJ, Robertson, MM, Kurlan, R, Liu, C, Gibbs, JR, Singleton, A, North American Brain Expression Consortium, Hardy, J, UK Human Brain Expression Database, Strengman, E, Ophoff, RA, Wagner, M, Moessner, R, Mirel, DB, Posthuma, D, Sabatti, C, Eskin, E, Conti, DV, Knowles, JA, Ruiz-Linares, A, Rouleau, GA, Purcell, S, Heutink, P, Oostra, BA, McMahon, WM, Freimer, NB, Cox, NJ, and Pauls, DL

Subjects
North American Brain Expression Consortium, UK Human Brain Expression Database, Chromosomes, Human, Pair 9, Humans, Tourette Syndrome, Genetic Predisposition to Disease, Fibrillar Collagens, Case-Control Studies, Obsessive-Compulsive Disorder, Attention Deficit Disorder with Hyperactivity, Genotype, Polymorphism, Single Nucleotide, International Cooperation, Adolescent, Adult, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Young Adult, White People, Genetics, Human Genome, Mental Health, Brain Disorders, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, genetics, GWAS, neurodevelopmental disorder, tics, Tourette's syndrome, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P

Published
2013

3. A genome-wide meta-analysis of association studies of Cloninger's Temperament Scales.

Author

Service, SK, Verweij, KJH, Lahti, J, Congdon, E, Ekelund, J, Hintsanen, M, Räikkönen, K, Lehtimäki, T, Kähönen, M, Widen, E, Taanila, A, Veijola, J, Heath, AC, Madden, PAF, Montgomery, GW, Sabatti, C, Järvelin, M-R, Palotie, A, Raitakari, O, Viikari, J, Martin, NG, Eriksson, JG, Keltikangas-Järvinen, L, Wray, NR, and Freimer, NB

Subjects
Humans, Cohort Studies, Longitudinal Studies, Reproducibility of Results, Personality, Temperament, Personality Inventory, Psychometrics, Twins, Genotype, Linkage Disequilibrium, Phenotype, Genetic Heterogeneity, Polymorphism, Single Nucleotide, Adult, Middle Aged, Australia, Finland, Female, Male, Genome-Wide Association Study, association, genetics, genome-wide, meta-analysis, personality, temperament, Polymorphism, Single Nucleotide, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P

Published
2012

4. The dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth

Author

Ghiani, CA, Starcevic, M, Rodriguez-Fernandez, IA, Nazarian, R, Cheli, VT, Chan, LN, Malvar, JS, de Vellis, J, Sabatti, C, and Dell'Angelica, EC

Subjects
Schizophrenia, Mental Health, Brain Disorders, Genetics, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, Mental health, Neurological, Analysis of Variance, Animals, Animals, Newborn, Carrier Proteins, Cattle, Cells, Cultured, Dysbindin, Dystrophin-Associated Proteins, Embryo, Mammalian, Gene Expression Regulation, Developmental, Hippocampus, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Nerve Tissue Proteins, Neurites, Neurons, Protein Binding, Protein Transport, Qa-SNARE Proteins, Recombinant Proteins, SNARE Proteins, Synaptosomal-Associated Protein 25, Vesicle-Associated Membrane Protein 2, schizophrenia, DTNBP1, pallidin, synaptosomal-associated protein, biological plausibility, neurite extension, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Previous studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis.

Published
2010

6. Increased activation product of Complement 4 protein in plasma of individuals with schizophrenia

Author

Kalinowski, A., primary, Liliental, J., additional, Anker, L., additional, Linkovski, O., additional, Culbertson, C., additional, Hall, J., additional, Pattni, R., additional, Sabatti, C., additional, Noordsy, D., additional, Hallmayer, J.F., additional, Mellins, E., additional, Ballon, J.S., additional, O'Hara, R., additional, Levinson, D.F., additional, and Urban, A.E., additional

Published
2021
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7. Searching for robust associations with a multi-environment knockoff filter.

Author

Li, S, Sesia, M, Romano, Y, Candès, E, and Sabatti, C

Subjects
GENOME-wide association studies, FALSE discovery rate, CAUSAL inference
Abstract

In this article we develop a method based on model-X knockoffs to find conditional associations that are consistent across environments, while controlling the false discovery rate. The motivation for this problem is that large datasets may contain numerous associations that are statistically significant and yet misleading, as they are induced by confounders or sampling imperfections. However, associations replicated under different conditions may be more interesting. In fact, sometimes consistency provably leads to valid causal inferences even if conditional associations do not. Although the proposed method is widely applicable, in this paper we highlight its relevance to genome-wide association studies, in which robustness across populations with diverse ancestries mitigates confounding due to unmeasured variants. The effectiveness of this approach is demonstrated by simulations and applications to UK Biobank data. [ABSTRACT FROM AUTHOR]

Published
2022
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15. Gene hunting with hidden Markov model knockoffs.

Author

Sesia, M, Sabatti, C, and Candès, E J

Subjects
*GENETIC algorithms, *PHENOTYPES, *HIDDEN Markov models, *FALSE positive error, *PROBLEM solving
Abstract

Modern scientific studies often require the identification of a subset of explanatory variables. Several statistical methods have been developed to automate this task, and the framework of knockoffs has been proposed as a general solution for variable selection under rigorous Type I error control, without relying on strong modelling assumptions. In this paper, we extend the methodology of knockoffs to problems where the distribution of the covariates can be described by a hidden Markov model. We develop an exact and efficient algorithm to sample knockoff variables in this setting and then argue that, combined with the existing selective framework, this provides a natural and powerful tool for inference in genome-wide association studies with guaranteed false discovery rate control. We apply our method to datasets on Crohn's disease and some continuous phenotypes. [ABSTRACT FROM AUTHOR]

Published
2019
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20. Disruption of the neurexin 1 gene is associated with schizophrenia

Author

Toulopoulou, T, Wiersma, D, Murray, R, Ruggeri, M, Tosato, S, Bonetto, C, Steinberg, S, Sigurdsson, E, Sigmundsson, T, Petursson, H, Gylfason, A, Olason, PI, Hardarsson, G, Jonsdottir, GA, Cahn, W, de Haan, L, Krabbendam, L, MyinGermeys, I, Werge, T, Kiemeney, LA, Franke, B, Pietiläinen, OPH, Picchioni, M, Vassos, E, Ettinger, U, Rietschel, M, Gustafsson, O, BuizerVoskamp, JE, Fossdal, R, Giegling, I, Sabatti, C, Ophoff, RA, Möller, HJ, Hartmann, AM, Hoffmann, P, Crombie, C, Rujescu, D, Veltman, J, Fraser, G, St Clair, D, Peltonen, L, Stefansson, K, Barnes, MR, Ingason, A, Stefansson, H, Nöthen, MM, Walker, N, Lonnqvist, J, Suvisaari, J, TuulioHenriksson, A, Djurovic, S, Collier, DA, Kahn, RS, Melle, I, Andreassen, OA, Hansen, T, Linszen, D, von Os, J, Bramon, E, Cichon, S, Bruggeman, R, ANS - Amsterdam Neuroscience, Adult Psychiatry, Germeys, Inez, Clinical Child and Family Studies, LEARN! - Brain, learning and development, and Faculteit Medische Wetenschappen/UMCG

Subjects
Male, Genetics and epigenetic pathways of disease [NCMLS 6], Gene Dosage, Aetiology, screening and detection [ONCOL 5], CARDIO-FACIAL SYNDROME, 0302 clinical medicine, Gene Duplication, Gene duplication, Perception and Action [DCN 1], HUMAN GENOME, Copy-number variation, European Continental Ancestry Group/genetics, Neural Cell Adhesion Molecules, POPULATION, Genetics (clinical), RISK, Genetics, 0303 health sciences, education.field_of_study, Schizophrenia/*genetics, REARRANGEMENTS, General Medicine, Exons, Nerve Tissue Proteins/*genetics, Penetrance, 3. Good health, Female, Molecular Sequence Numbers, Functional Neurogenomics [DCN 2], Adult, Psychosis, Adolescent, Cell Adhesion Molecules, Neuronal, Population, European Continental Ancestry Group, Nerve Tissue Proteins, COPY-NUMBER VARIATION, Biology, Gene dosage, Article, White People, STRUCTURAL VARIANTS, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Young Adult, Translational research [ONCOL 3], mental disorders, medicine, Humans, MICRODELETION, Genetic Predisposition to Disease, Gene Silencing, education, Molecular Biology, 030304 developmental biology, Genetic association, Hereditary cancer and cancer-related syndromes [ONCOL 1], AUTISM SPECTRUM DISORDER, Calcium-Binding Proteins, Case-Control Studies, Gene Deletion, Breakpoint, ADVANCING PATERNAL AGE, medicine.disease, Schizophrenia, 030217 neurology & neurosurgery
Abstract

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia. © The Author 2008. Published by Oxford University Press. All rights reserved., link_to_OA_fulltext

Published
2009

21. Large recurrent microdeletions associated with schizophrenia

Author

Toulopoulou, T, Franke, B, Crombie, C, Fossdal, R, Sigmundsson, T, BuizerVoskamp, JE, Hansen, T, Jakobsen, KD, Muglia, P, Francks, C, Matthews, PM, Murray, R, Ruggeri, M, Sabatti, C, Gylfason, A, Halldorsson, BV, Vassos, E, Tosato, S, Walshe, M, Freimer, NB, Gulcher, JR, Gudbjartsson, D, Thorsteinsdottir, U, Kong, A, Thorgeirsson, TE, Olesen, J, Vasilescu, C, Andreassen, OA, Melle, I, Mühleisen, TW, Wang, AG, Ullum, H, Need, AC, Sigurdsson, A, Jonasdottir, A, Djurovic, S, Ophoff, RA, Georgi, A, Rietschel, M, Werge, T, Bjornsson, A, Mattiasdottir, S, Blondal, T, Haraldsson, M, Petursson, H, MyinGermeys, I, Krabbendam, L, De Haan, L, Cahn, W, Bruggeman, R, Wiersma, D, Goldstein, DB, Nöthen, MM, Peltonen, L, Van Os, J, Linszen, DH, Kahn, RS, Stefansson, K, Magnusdottir, BB, Di Forti, M, Bramon, E, Paunio, T, TuulioHenriksson, A, Giegling, I, Möller, HJ, Suvisaari, J, Hartmann, A, Shianna, KV, Ge, D, Lonnqvist, J, Collier, DA, Walker, N, Li, T, Fraser, G, Ingason, A, Steinberg, S, Sigurdsson, E, St Clair, D, Kiemeney, LA, Stefansson, H, Rujescu, D, Cichon, S, Pietiläinen, OPH, ANS - Amsterdam Neuroscience, and Adult Psychiatry

Subjects
Schizophrenia/genetics, Genetics and epigenetic pathways of disease [NCMLS 6], Loss of Heterozygosity, Aetiology, screening and detection [ONCOL 5], Bioinformatics, China, Chromosomes, Human, Pair 1/genetics, Pair 15/genetics, Europe, Gene Dosage/genetics, Genetic Predisposition to Disease/genetics, Genome, Human/genetics, Genotype, Models, Genetic, Polymorphism, Single Nucleotide/genetics, Psychotic Disorders/genetics, Sequence Deletion/genetics, Perception and Action [DCN 1], Determinants in Health and Disease [EBP 1], Copy-number variation, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], Genetics, education.field_of_study, Multidisciplinary, biology, CHRNA7, Fragile X syndrome, References (31) View In Table Layout, Schizophrenia, Functional Neurogenomics [DCN 2], Psychosis, Population, Single-nucleotide polymorphism, Article, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], Cognitive neurosciences [UMCN 3.2], Translational research [ONCOL 3], mental disorders, medicine, education, Hereditary cancer and cancer-related syndromes [ONCOL 1], medicine.disease, Genetic defects of metabolism [UMCN 5.1], biology.protein, Autism
Abstract

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. ©2008 Macmillan Publishers Limited. All rights reserved., link_to_OA_fulltext

Published
2008

22. Large recurrent microdeletions associated with schizophrenia [Letter to Nature]

Author

Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J., Hansen, T., Jakobsen, K., Muglia, P., Francks, C., Matthews, P., Gylfason, A., Halldorsson, B., Gudbjartsson, D., Thorgeirsson, T., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B., Giegling, I., Möller, H., Hartmann, A., Shianna, K., Ge, D., Need, A., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T., Wang, A., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L., Franke, B., Sabatti, C., Freimer, N., Gulcher, J., Thorsteinsdottir, U., Kong, A., Andreassen, O., Ophoff, R., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D., Nothen, M., Peltonen, L., Collier, D., St. Clair, D., and Stefansson, K.

Subjects
mental disorders
Abstract

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Published
2008

23. Increased paternal age and the influence on burden of genomic copy number variation in the general population

Author

Buizer-Voskamp, J.E., Blauw, H.M., Boks, M.P., Eijk, K.R. van, Veldink, J.H., Hennekam, E.A., Vorstman, J.A., Mulder, F., Tiemeier, H., Uitterlinden, A.G., Kiemeney, L.A.L.M., Berg, L.H. van den, Kahn, R.S., Sabatti, C., Ophoff, R.A., Buizer-Voskamp, J.E., Blauw, H.M., Boks, M.P., Eijk, K.R. van, Veldink, J.H., Hennekam, E.A., Vorstman, J.A., Mulder, F., Tiemeier, H., Uitterlinden, A.G., Kiemeney, L.A.L.M., Berg, L.H. van den, Kahn, R.S., Sabatti, C., and Ophoff, R.A.

Abstract

Item does not contain fulltext, Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father's age may be independent disease risk factors.

Published
2013

24. EDU-CARE®, a randomised, multicentre, parallel group study on education and quality of life in COPD

Author

Carone, M., Bertolott, G., Cerveri, I., De Benedetto, F., Fogliani, V., Nardini, S., Portalone, L., Rossi, A., Sanguinetti, C. M., Schiavina, M., Manenti, C. F. Donner on behalf of Edu-Care working group(G., Zanello, A., Balestra, F., Di Gregorio, A., Benamati, G., Quaglia, A., Bonavia, M., Pela, R., Mignini, D., Occhionero, L., Terreno, M., D’Avanzo, Areopagita, A., De Tullio, R., Gatta, E., Moretti, A. M., Brindicci, C., Arnone, P., Cavalli, A., Prati, M., Fabiani, A., Pederzoli, M., Donazzan, G., Begher, G., Tassi, G., Nava, A. M., Sabatti, C., Dal Negro, R., Trevisan, F., Pomari, C., Ligia, G. P., Sortino, E., Rosetti, L., Murgia, A., Piccolini, E., Casazza, M. P., Cioffi, R., Di Salvatore, F., Mirabella, S., Porto, G., De Francesca, F., Polverino, M., Santoriello, C., Fiorenzano, G., D’Intino, A., Idotta, G., Marcolongo, A., Balduin, R., Macaluso, S., Sugamiele, M., Peralta, G., Potena, A., Piattella, M., Corrado, A., Villella, G., Vincenzi, U., Cisternino, L., Fiorentini, F., Colinelli, C., Franco, C., Di Tommasi, M., Perrella, A., Dottorini, M. L., Branca, M. G., Peccini, F., Greco, P., Farris, B., Colorizio, V., Meccia, A., Munafò, G., Zanini, R., Sarni, A., Scoditti, S., Toma, P., Pancosta, G., Marchesani, F., Cipolla, G., Roggi, G., Monacci, A., Ruggeri, S., D’Anneo, R., Centanni, S., Legnani, P. Carlucci – Milano: D., Raiteri, D., Vitale, T., Cirocco, A., Carifi, S., Cocco, G., Iodice, F., De Michele, F., Cecarini, L., Ferrara, G., Di Gregorio, S., Fulgoni, P., Dottorini, M., Baglioni, S., Eslami, A., Ugolini, M., Dennetta, D., Bottrighi, P., Innocenti, F., Fabbri, A., Sanna, A., Celano, M., Tobia, N., Battiloro, R., Lamorgese, V., Castellana, G., Agati, G., Costarella, L., Altieri, A. M., D’Antonio, S., Dominici, M., De Angelis, G., Propati, A., Sini, A., Albergati, M., Viola, B., Rizzo, S., Dalmasso, F., Cordola, G., Santelli, G., Faccini, E., Confalonieri, M, Nabergoj, M., Ciani, F., Basile, G., Cipriani, A., Broseghini, C., Festi, G., Donner, C. F., D’Anna, S., Barbano, G., and G. Bazzerla).

Subjects
quality of life, copd, educational program
Published
2002

25. A genome-wide meta-analysis of association studies of Cloninger's Temperament Scales

Author

Service, S.K., Verweij, K.J.H., Lahti, J., Congdon, E., Ekelund, J., Hintsanen, M., Raikkonen, K., Lehtimaki, T., Kahonen, M., Widen, E., Taanila, A., Veijola, J., Heath, A.C., Madden, P.A.F., Montgomery, G.W., Sabatti, C., Jarvelin, M.R., Palotie, A., Raitakari, O., Viikari, J., Martin, N.G., Eriksson, J.G., Keltikangas-Jarvinen, L., Wray, N.R., Freimer, N.B., Service, S.K., Verweij, K.J.H., Lahti, J., Congdon, E., Ekelund, J., Hintsanen, M., Raikkonen, K., Lehtimaki, T., Kahonen, M., Widen, E., Taanila, A., Veijola, J., Heath, A.C., Madden, P.A.F., Montgomery, G.W., Sabatti, C., Jarvelin, M.R., Palotie, A., Raitakari, O., Viikari, J., Martin, N.G., Eriksson, J.G., Keltikangas-Jarvinen, L., Wray, N.R., and Freimer, N.B.

Abstract

Contains fulltext : 156129.pdf (publisher's version ) (Open Access), Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11 000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P < 1.25 x 10(-8), with correction for testing four scales) accounting for >= 0.4% of the phenotypic variance in temperament scales. Using meta-analysis techniques, gene-based tests and pathway analysis we have tested over 1.2 million single-nucleotide polymorphisms (SNPs) for association to each of the four temperament dimensions. We did not discover any SNPs, genes, or pathways to be significantly related to the four temperament dimensions, after correcting for multiple testing. Less than 1% of the variability in any temperament dimension appears to be accounted for by a risk score derived from the SNPs showing strongest association to the temperament dimensions. Elucidation of genetic loci significantly influencing temperament and personality will require potentially very large samples, and/or a more refined phenotype. Item response theory methodology may be a way to incorporate data from cohorts assessed with multiple personality instruments, and might be a method by which a large sample of a more refined phenotype could be acquired.

Published
2012

26. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., Kathiresan, S., DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., and Kathiresan, S.

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Published
2012

27. Genome-wide analysis shows increased frequency of copy number variation deletions in dutch schizophrenia patients

Author

Buizer-Voskamp, J.E., Muntjewerff, J.W., Strengman, E., Sabatti, C., Stefansson, H., Vorstman, J.A., Ophoff, R.A., Buizer-Voskamp, J.E., Muntjewerff, J.W., Strengman, E., Sabatti, C., Stefansson, H., Vorstman, J.A., and Ophoff, R.A.

Abstract

Item does not contain fulltext, BACKGROUND: Since 2008, multiple studies have reported on copy number variations (CNVs) in schizophrenia. However, many regions are unique events with minimal overlap between studies. This makes it difficult to gain a comprehensive overview of all CNVs involved in the etiology of schizophrenia. We performed a systematic CNV study on the basis of a homogeneous genome-wide dataset aiming at all CNVs >/= 50 kilobase pair. We complemented this analysis with a review of cytogenetic and chromosomal abnormalities for schizophrenia reported in the literature with the purpose of combining classical genetic findings and our current understanding of genomic variation. METHODS: We investigated 834 Dutch schizophrenia patients and 672 Dutch control subjects. The CNVs were included if they were detected by QuantiSNP (http://www.well.ox.ac.uk/QuantiSNP/) as well as PennCNV (http://www.neurogenome.org/cnv/penncnv/) and contain known protein coding genes. The integrated identification of CNV regions and cytogenetic loci indicates regions of interest (cytogenetic regions of interest [CROIs]). RESULTS: In total, 2437 CNVs were identified with an average number of 2.1 CNVs/subject for both cases and control subjects. We observed significantly more deletions but not duplications in schizophrenia cases versus control subjects. The CNVs identified coincide with loci previously reported in the literature, confirming well-established schizophrenia CROIs 1q42 and 22q11.2 as well as indicating a potentially novel CROI on chromosome 5q35.1. CONCLUSIONS: Chromosomal deletions are more prevalent in schizophrenia patients than in healthy subjects and therefore confer a risk factor for pathogenicity. The combination of our CNV data with previously reported cytogenetic abnormalities in schizophrenia provides an overview of potentially interesting regions for positional candidate genes.

Published
2011

28. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, T.M. (Tanya), Musunuru, K. (Kiran), Smith, A.V. (Albert Vernon), Edmondson, A.C. (Andrew), Stylianou, I.M. (Ioannis), Koseki, M. (Masahiro), Pirruccello, J.P. (James), Ripatti, S. (Samuli), Chasman, D.I. (Daniel), Willer, C.J. (Cristen), Johansen, C.T. (Christopher), Fouchier, S.W. (Sigrid), Isaacs, A.J. (Aaron), Peloso, G.M. (Gina), Barbalic, M. (maja), Ricketts, S.L. (Sally), Bis, J.C. (Joshua), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), Feitosa, M.F. (Mary Furlan), Chambers, J. (John), Orho-Melander, M. (Marju), Melander, O. (Olle), Johnson, T. (Toby), Li, X. (Xiaohui), Guo, X. (Xiuqing), Shin Cho, Y. (Yoon), Jin Go, M. (Min), Jin Kim, Y. (Young), Lee, J.Y. (Jong Young), Park, T. (Taesung), Kim, Y-J. (Yong-Jin), Sim, X. (Xueling), Twee-Hee Ong, R. (Rick), Croteau-Chonka, D.C. (Damien), Lange, L.A. (Leslie), Song, K. (Kijoung), Zhao, J.H. (Jing Hua), Yuan, X. (Xin), Luan, J., Lamina, C. (Claudia), Ziegler, A. (Andreas), Zhang, W. (Weibo), Zee, R.Y.L. (Robert), Wright, A.F. (Alan), Witteman, J.C.M. (Jacqueline), Wilson, J.F. (James), Willemsen, G.A.H.M. (Gonneke), Wichmann, H.E. (Heinz Erich), Whitfield, J. (John), Waterworth, D. (Dawn), Wareham, N.J. (Nick), Waeber, G. (Gérard), Vollenweider, P. (Peter), Voight, B.F. (Benjamin), Vitart, V. (Veronique), Uitterlinden, A.G. (André), Uda, M. (Manuela), Tuomilehto, J. (Jaakko), Thompson, J.R. (John), Tanaka, T. (Toshiko), Surakka, I. (Ida), Stringham, H.M. (Heather), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Smit, J.H. (Johannes), Sinisalo, J. (Juha), Silander, K. (Kaisa), Sijbrands, E.J.G. (Eric), Scuteri, A. (Angelo), Scott, J. (James), Schlessinger, D. (David), Sanna, S. (Serena), Salomaa, V. (Veikko), Saharinen, J. (Juha), Sabatti, C. (Chiara), Ruokonen, A. (Aimo), Rudan, I. (Igor), Rose, L.M. (Lynda), Roberts, R. (Robert), Rieder, M. (Mark), Psaty, B.M. (Bruce), Pramstaller, P.P. (Peter Paul), Pichler, I. (Irene), Perola, M. (Markus), Penninx, B.W.J.H. (Brenda), Pedersen, N.L. (Nancy), Pattaro, C. (Cristian), Parker, A.N. (Alex), Pare, G. (Guillaume), Oostra, B.A. (Ben), Nieminen, M.S. (Markku), Nickerson, D.A. (Deborah), Montgomery, G.W. (Grant), Meitinger, T. (Thomas), McPherson, R. (Ruth), McCarthy, M.I. (Mark), McArdle, W.L. (Wendy), Masson, D. (David), Martin, N.G. (Nicholas), Marroni, F. (Fabio), Mangino, M. (Massimo), Magnusson, P.K. (Patrik), Lucas, G. (Gavin), Luben, R.N. (Robert), Loos, R.J.F. (Ruth), Lokki, M.L., Lettre, G. (Guillaume), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lakatta, E. (Edward), Laaksonen, R. (Reijo), Kyvik, K.O. (Kirsten Ohm), Kronenberg, F. (Florian), König, I.R. (Inke), Khaw, K-T. (Kay-Tee), Kaprio, J. (Jaakko), Kaplan, R.C. (Robert), Johansson, A. (Åsa), Jarvelin, M.-R. (Marjo-Riitta), Cecile, A. (A.), Ingelsson, E. (Erik), Igl, W. (Wilmar), Hovingh, G.K. (Kees), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Hicks, A.A. (Andrew), Hengstenberg, C. (Christian), Heid, I.M. (Iris), Hayward, C. (Caroline), Havulinna, A.S. (Aki), Hastie, N. (Nick), Harris, T.B. (Tamara), Haritunians, T. (Talin), Hall, A.S. (Alistair), Gyllensten, U. (Ulf), Guiducci, C. (Candace), Groop, L. (Leif), Gonzalez, E. (Elena), Gieger, C. (Christian), Freimer, N.B. (Nelson), Ferrucci, L. (Luigi), Erdmann, J. (Jeanette), Elliott, P. (Paul), Ejebe, K.G. (Kenechi), Döring, A. (Angela), Dominiczak, A. (Anna), Demissie, S. (Serkalem), Deloukas, P. (Panagiotis), Geus, E.J.C. (Eco) de, Faire, U. (Ulf) de, Crawford, G. (Gabe), Collins, F.S. (Francis), Chen, C. (Chao), Caulfield, M. (Mark), Campbell, H. (Harry), Burtt, N.P. (Noël), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Boekholdt, S.M. (Matthijs), Bergman, R.N. (Richard), Barroso, I.E. (Inês), Bandinelli, S. (Stefania), Ballantyne, C. (Christie), Assimes, T.L. (Themistocles), Quertermous, T. (Thomas), Altshuler, D. (David), Seielstad, M. (Mark), Wong, T.Y. (Tien Yin), Tai, E.S. (Shyong), Feranil, A.B. (Alan), Kuzawa, C.W. (Christopher), Adair, L.S. (Linda), Taylor, H.A. (Herman), Borecki, I.B. (Ingrid), Gabriel, S.B. (Stacey), Holm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Gudnason, V. (Vilmundur), Krauss, R.M. (Ronald), Mohlke, K.L. (Karen), Ordovas, J.M. (Jose), Munroe, P. (Patricia), Kooner, J.S. (Jaspal), Tall, A.R. (Alan), Hegele, R.A. (Robert), Kastelein, J.J.P. (John), Schadt, E.E. (Eric), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Strachan, D.P. (David), Mooser, V. (Vincent), Zwart, J-A. (John-Anker), Reilly, M.P. (Muredach), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Cupples, L.A. (Adrienne), Sandhu, M.S. (Manjinder), Ridker, P.M. (Paul), Rader, D.J. (Daniel), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Kathiresan, S. (Sekar), O'Donnell, C.J. (Christopher), Teslovich, T.M. (Tanya), Musunuru, K. (Kiran), Smith, A.V. (Albert Vernon), Edmondson, A.C. (Andrew), Stylianou, I.M. (Ioannis), Koseki, M. (Masahiro), Pirruccello, J.P. (James), Ripatti, S. (Samuli), Chasman, D.I. (Daniel), Willer, C.J. (Cristen), Johansen, C.T. (Christopher), Fouchier, S.W. (Sigrid), Isaacs, A.J. (Aaron), Peloso, G.M. (Gina), Barbalic, M. (maja), Ricketts, S.L. (Sally), Bis, J.C. (Joshua), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), Feitosa, M.F. (Mary Furlan), Chambers, J. (John), Orho-Melander, M. (Marju), Melander, O. (Olle), Johnson, T. (Toby), Li, X. (Xiaohui), Guo, X. (Xiuqing), Shin Cho, Y. (Yoon), Jin Go, M. (Min), Jin Kim, Y. (Young), Lee, J.Y. (Jong Young), Park, T. (Taesung), Kim, Y-J. (Yong-Jin), Sim, X. (Xueling), Twee-Hee Ong, R. (Rick), Croteau-Chonka, D.C. (Damien), Lange, L.A. (Leslie), Song, K. (Kijoung), Zhao, J.H. (Jing Hua), Yuan, X. (Xin), Luan, J., Lamina, C. (Claudia), Ziegler, A. (Andreas), Zhang, W. (Weibo), Zee, R.Y.L. (Robert), Wright, A.F. (Alan), Witteman, J.C.M. (Jacqueline), Wilson, J.F. (James), Willemsen, G.A.H.M. (Gonneke), Wichmann, H.E. (Heinz Erich), Whitfield, J. (John), Waterworth, D. (Dawn), Wareham, N.J. (Nick), Waeber, G. (Gérard), Vollenweider, P. (Peter), Voight, B.F. (Benjamin), Vitart, V. (Veronique), Uitterlinden, A.G. (André), Uda, M. (Manuela), Tuomilehto, J. (Jaakko), Thompson, J.R. (John), Tanaka, T. (Toshiko), Surakka, I. (Ida), Stringham, H.M. (Heather), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Smit, J.H. (Johannes), Sinisalo, J. (Juha), Silander, K. (Kaisa), Sijbrands, E.J.G. (Eric), Scuteri, A. (Angelo), Scott, J. (James), Schlessinger, D. (David), Sanna, S. (Serena), Salomaa, V. (Veikko), Saharinen, J. (Juha), Sabatti, C. (Chiara), Ruokonen, A. (Aimo), Rudan, I. (Igor), Rose, L.M. (Lynda), Roberts, R. (Robert), Rieder, M. (Mark), Psaty, B.M. (Bruce), Pramstaller, P.P. (Peter Paul), Pichler, I. (Irene), Perola, M. (Markus), Penninx, B.W.J.H. (Brenda), Pedersen, N.L. (Nancy), Pattaro, C. (Cristian), Parker, A.N. (Alex), Pare, G. (Guillaume), Oostra, B.A. (Ben), Nieminen, M.S. (Markku), Nickerson, D.A. (Deborah), Montgomery, G.W. (Grant), Meitinger, T. (Thomas), McPherson, R. (Ruth), McCarthy, M.I. (Mark), McArdle, W.L. (Wendy), Masson, D. (David), Martin, N.G. (Nicholas), Marroni, F. (Fabio), Mangino, M. (Massimo), Magnusson, P.K. (Patrik), Lucas, G. (Gavin), Luben, R.N. (Robert), Loos, R.J.F. (Ruth), Lokki, M.L., Lettre, G. (Guillaume), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Lakatta, E. (Edward), Laaksonen, R. (Reijo), Kyvik, K.O. (Kirsten Ohm), Kronenberg, F. (Florian), König, I.R. (Inke), Khaw, K-T. (Kay-Tee), Kaprio, J. (Jaakko), Kaplan, R.C. (Robert), Johansson, A. (Åsa), Jarvelin, M.-R. (Marjo-Riitta), Cecile, A. (A.), Ingelsson, E. (Erik), Igl, W. (Wilmar), Hovingh, G.K. (Kees), Hottenga, J.J. (Jouke Jan), Hofman, A. (Albert), Hicks, A.A. (Andrew), Hengstenberg, C. (Christian), Heid, I.M. (Iris), Hayward, C. (Caroline), Havulinna, A.S. (Aki), Hastie, N. (Nick), Harris, T.B. (Tamara), Haritunians, T. (Talin), Hall, A.S. (Alistair), Gyllensten, U. (Ulf), Guiducci, C. (Candace), Groop, L. (Leif), Gonzalez, E. (Elena), Gieger, C. (Christian), Freimer, N.B. (Nelson), Ferrucci, L. (Luigi), Erdmann, J. (Jeanette), Elliott, P. (Paul), Ejebe, K.G. (Kenechi), Döring, A. (Angela), Dominiczak, A. (Anna), Demissie, S. (Serkalem), Deloukas, P. (Panagiotis), Geus, E.J.C. (Eco) de, Faire, U. (Ulf) de, Crawford, G. (Gabe), Collins, F.S. (Francis), Chen, C. (Chao), Caulfield, M. (Mark), Campbell, H. (Harry), Burtt, N.P. (Noël), Bonnycastle, L.L. (Lori), Boomsma, D.I. (Dorret), Boekholdt, S.M. (Matthijs), Bergman, R.N. (Richard), Barroso, I.E. (Inês), Bandinelli, S. (Stefania), Ballantyne, C. (Christie), Assimes, T.L. (Themistocles), Quertermous, T. (Thomas), Altshuler, D. (David), Seielstad, M. (Mark), Wong, T.Y. (Tien Yin), Tai, E.S. (Shyong), Feranil, A.B. (Alan), Kuzawa, C.W. (Christopher), Adair, L.S. (Linda), Taylor, H.A. (Herman), Borecki, I.B. (Ingrid), Gabriel, S.B. (Stacey), Holm, H. (Hilma), Thorsteinsdottir, U. (Unnur), Gudnason, V. (Vilmundur), Krauss, R.M. (Ronald), Mohlke, K.L. (Karen), Ordovas, J.M. (Jose), Munroe, P. (Patricia), Kooner, J.S. (Jaspal), Tall, A.R. (Alan), Hegele, R.A. (Robert), Kastelein, J.J.P. (John), Schadt, E.E. (Eric), Rotter, J.I. (Jerome), Boerwinkle, E.A. (Eric), Strachan, D.P. (David), Mooser, V. (Vincent), Zwart, J-A. (John-Anker), Reilly, M.P. (Muredach), Samani, N.J. (Nilesh), Schunkert, H. (Heribert), Cupples, L.A. (Adrienne), Sandhu, M.S. (Manjinder), Ridker, P.M. (Paul), Rader, D.J. (Daniel), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Kathiresan, S. (Sekar), and O'Donnell, C.J. (Christopher)

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<-10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010
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29. Biological, clinical and population relevance of 95 loci for blood lipids

Author

Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YS, Go, MJ, Kim, YJ, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RT-H, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, J, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Koenig, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, Janssens, ACJW, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, Kathiresan, S, Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, X, Guo, X, Li, M, Cho, YS, Go, MJ, Kim, YJ, Lee, J-Y, Park, T, Kim, K, Sim, X, Ong, RT-H, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, J, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, H-E, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, AG, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, BA, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, M-L, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Koenig, IR, Khaw, K-T, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, M-R, Janssens, ACJW, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, J-J, Hofman, A, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, Y-DI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, E-S, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, van Duijn, CM, Peltonen, L, Abecasis, GR, Boehnke, M, and Kathiresan, S

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Published
2010

30. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Author

Aulchenko, Y.S. (Yurii), Ripatti, S. (Samuli), Lindqvist, I. (Ida), Boomsma, D.I. (Dorret), Heid, I.M. (Iris), Pramstaller, P.P. (Peter Paul), Penninx, B.W.J.H. (Brenda), Janssens, A.C.J.W. (Cécile), Wilson, J.F. (James), Spector, T.D. (Timothy), Martin, N.G. (Nicholas), Pedersen, N.L. (Nancy), Kyvik, K.O. (Kirsten Ohm), Kaprio, J. (Jaakko), Hofman, A. (Albert), Freimer, N.B. (Nelson), Jarvelin, M.-R. (Marjo-Riitta), Gyllensten, U. (Ulf), Campbell, H. (Harry), Rudan, I. (Igor), Johansson, A. (Åsa), Marroni, F. (Fabio), Hayward, C. (Caroline), Vitart, V. (Veronique), Jonasson, I. (Inger), Pattaro, C. (Cristian), Wright, A. (Alan), Hastie, N. (Nick), Pichler, I. (Irene), Hicks, A.A. (Andrew), Falchi, M. (Mario), Willemsen, G.A.H.M. (Gonneke), Hottenga, J.J. (Jouke Jan), Geus, E.J.C. (Eco) de, Montgomery, G.W. (Grant), Whitfield, J. (John), Magnusson, P. (Patrik), Saharinen, J. (Juha), Perola, M. (Markus), Silander, K. (Kaisa), Isaacs, A.J. (Aaron), Sijbrands, E.J.G. (Eric), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Oostra, B.A. (Ben), Elliott, P. (Paul), Ruokonen, A. (Aimo), Sabatti, C. (Chiara), Gieger, C. (Christian), Meitinger, T. (Thomas), Kronenberg, F. (Florian), Döring, A. (Angela), Wichmann, H.E. (Erich), Smit, J.H. (Johannes), McCarthy, M.I. (Mark), Tikka-Kleemola, P. (Päivi), Peltonen, L. (Leena Johanna), Aulchenko, Y.S. (Yurii), Ripatti, S. (Samuli), Lindqvist, I. (Ida), Boomsma, D.I. (Dorret), Heid, I.M. (Iris), Pramstaller, P.P. (Peter Paul), Penninx, B.W.J.H. (Brenda), Janssens, A.C.J.W. (Cécile), Wilson, J.F. (James), Spector, T.D. (Timothy), Martin, N.G. (Nicholas), Pedersen, N.L. (Nancy), Kyvik, K.O. (Kirsten Ohm), Kaprio, J. (Jaakko), Hofman, A. (Albert), Freimer, N.B. (Nelson), Jarvelin, M.-R. (Marjo-Riitta), Gyllensten, U. (Ulf), Campbell, H. (Harry), Rudan, I. (Igor), Johansson, A. (Åsa), Marroni, F. (Fabio), Hayward, C. (Caroline), Vitart, V. (Veronique), Jonasson, I. (Inger), Pattaro, C. (Cristian), Wright, A. (Alan), Hastie, N. (Nick), Pichler, I. (Irene), Hicks, A.A. (Andrew), Falchi, M. (Mario), Willemsen, G.A.H.M. (Gonneke), Hottenga, J.J. (Jouke Jan), Geus, E.J.C. (Eco) de, Montgomery, G.W. (Grant), Whitfield, J. (John), Magnusson, P. (Patrik), Saharinen, J. (Juha), Perola, M. (Markus), Silander, K. (Kaisa), Isaacs, A.J. (Aaron), Sijbrands, E.J.G. (Eric), Uitterlinden, A.G. (André), Witteman, J.C.M. (Jacqueline), Oostra, B.A. (Ben), Elliott, P. (Paul), Ruokonen, A. (Aimo), Sabatti, C. (Chiara), Gieger, C. (Christian), Meitinger, T. (Thomas), Kronenberg, F. (Florian), Döring, A. (Angela), Wichmann, H.E. (Erich), Smit, J.H. (Johannes), McCarthy, M.I. (Mark), Tikka-Kleemola, P. (Päivi), and Peltonen, L. (Leena Johanna)

Abstract

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10-8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10-11; LDL, P = 2.6 × 10-10), TMEM57 (TC, P = 5.4 × 10-10), CTCF-PRMT8 region (HDL, P = 8.3 × 10-16), DNAH11 (LDL, P = 6.1 × 10-9), FADS3-FADS2 (TC, P = 1.5 × 10-10; LDL, P = 4.4 × 10-13) and MADD-FOLH1 region (HDL, P = 6 × 10-11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

Published
2009
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31. Disruption of the neurexin 1 gene is associated with schizophrenia.

Author

Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A., Rujescu, D., Ingason, A., Cichon, S., Pietilainen, O.P.H., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A, Olason, P., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Moller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A.L.M., Franke, B., Veltman, J.A., Buizer-Voskamp, J.E., Sabatti, C., Ophoff, R.A., Rietschel, M., Nothen, Markus, Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., and Collier, D.A.

Abstract

Contains fulltext : 80670.pdf (publisher's version ) (Closed access), Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Published
2009

32. Large recurrent microdeletions associated with schizophrenia.

Author

Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A, Halldorsson, B.V., Gudbjartsson, D.F., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, B., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B, Nothen, Markus, Peltonen, L., Collier, D.A., St Clair, D., Stefansson, K., Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P.H., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A, Halldorsson, B.V., Gudbjartsson, D.F., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, B., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B, Nothen, Markus, Peltonen, L., Collier, D.A., St Clair, D., and Stefansson, K.

Abstract

Contains fulltext : 69527.pdf (publisher's version ) (Closed access)

Published
2008

33. Recurrent CNVs disrupt three candidate genes in schizophrenia patients.

Author

Vrijenhoek, T., Buizer-Voskamp, J.E., Stelt, I. van der, Strengman, E., Sabatti, C., Geurts van Kessel, A.H.M., Brunner, H.G., Ophoff, R.A., Veltman, J.A., Vrijenhoek, T., Buizer-Voskamp, J.E., Stelt, I. van der, Strengman, E., Sabatti, C., Geurts van Kessel, A.H.M., Brunner, H.G., Ophoff, R.A., and Veltman, J.A.

Abstract

Contains fulltext : 71232.pdf (publisher's version ) (Closed access), Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.

Published
2008

35. A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees

Author

Jasinska, A.J., primary, Service, S., additional, Jawaheer, D., additional, DeYoung, J., additional, Levinson, M., additional, Zhang, Z., additional, Kremeyer, B., additional, Muller, H., additional, Aldana, I., additional, Garcia, J., additional, Restrepo, G., additional, Lopez, C., additional, Palacio, C., additional, Duque, C., additional, Parra, M., additional, Vega, J., additional, Ortiz, D., additional, Bedoya, G., additional, Mathews, C., additional, Davanzo, P., additional, Fournier, E., additional, Bejarano, J., additional, Ramirez, M., additional, Araya Ortiz, C., additional, Araya, X., additional, Molina, J., additional, Sabatti, C., additional, Reus, V., additional, Ospina, J., additional, Macaya, G., additional, Ruiz-Linares, A., additional, and Freimer, N.B., additional

Published
2009
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45. The DYT1 phenotype and guidelines for diagnostic testing

Author

Bressman, S. B., primary, Sabatti, C., additional, Raymond, D., additional, de Leon, D., additional, Klein, C., additional, Kramer, P. L., additional, Brin, M. F., additional, Fahn, S., additional, Breakefield, X., additional, Ozelius, L. J., additional, and Risch, N. J., additional

Published
2000
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46. Bayesian analysis of haplotypes for linkage disequilibrium mapping.

Author

Liu, J S, Sabatti, C, Teng, J, Keats, B J, and Risch, N

Abstract

Haplotype analysis of disease chromosomes can help identify probable historical recombination events and localize disease mutations. Most available analyses use only marginal and pairwise allele frequency information. We have developed a Bayesian framework that utilizes full haplotype information to overcome various complications such as multiple founders, unphased chromosomes, data contamination, and incomplete marker data. A stochastic model is used to describe the dependence structure among several variables characterizing the observed haplotypes, for example, the ancestral haplotypes and their ages, mutation rate, recombination events, and the location of the disease mutation. An efficient Markov chain Monte Carlo algorithm was developed for computing the estimates of the quantities of interest. The method is shown to perform well in both real data sets (cystic fibrosis data and Friedreich ataxia data) and simulated data sets. The program that implements the proposed method, BLADE, as well as the two real datasets, can be obtained from http://www.fas.harvard.edu/~junliu/TechRept/01folder/diseq_prog.tar.gz.

Published
2001
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47. The DYT1phenotype and guidelines for diagnostic testing

Author

Bressman, S. B., Sabatti, C., Raymond, D., de Leon, D., Klein, C., Kramer, P. L., Brin, M. F., Fahn, S., Breakefield, X., Ozelius, L. J., and Risch, N. J.

Abstract

To develop diagnostic testing guidelines for the DYT1GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic features in affected DYT1deletion carriers.

Published
2000

49. Reconstructing DNA copy number by joint segmentation of multiple sequences

Author

Zhang Zhongyang, Lange Kenneth, and Sabatti Chiara

Subjects
Copy number variant, Copy number polymorphism, Fused lasso, Group fused lasso, MM algorithm, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Variations in DNA copy number carry information on the modalities of genome evolution and mis-regulation of DNA replication in cancer cells. Their study can help localize tumor suppressor genes, distinguish different populations of cancerous cells, and identify genomic variations responsible for disease phenotypes. A number of different high throughput technologies can be used to identify copy number variable sites, and the literature documents multiple effective algorithms. We focus here on the specific problem of detecting regions where variation in copy number is relatively common in the sample at hand. This problem encompasses the cases of copy number polymorphisms, related samples, technical replicates, and cancerous sub-populations from the same individual. Results We present a segmentation method named generalized fused lasso (GFL) to reconstruct copy number variant regions. GFL is based on penalized estimation and is capable of processing multiple signals jointly. Our approach is computationally very attractive and leads to sensitivity and specificity levels comparable to those of state-of-the-art specialized methodologies. We illustrate its applicability with simulated and real data sets. Conclusions The flexibility of our framework makes it applicable to data obtained with a wide range of technology. Its versatility and speed make GFL particularly useful in the initial screening stages of large data sets.

Published
2012
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50. Volume measures for linkage disequilibrium

Author

Lin Chia-Ho, Chen Yuguo, and Sabatti Chiara

Subjects
Genetics, QH426-470
Abstract

Abstract Background Defining measures of linkage disequilibrium (LD) that have good small sample properties and are applicable to multiallelic markers poses some challenges. The potential of volume measures in this context has been noted before, but their use has been hampered by computational challenges. Results We design a sequential importance sampling algorithm to evaluate volume measures on I × J tables. The algorithm is implemented in a C routine as a complement to exhaustive enumeration. We make the C code available as open source. We achieve fast and accurate evaluation of volume measures in two dimensional tables. Conclusion Applying our code to simulated and real datasets reinforces the belief that volume measures are a very useful tool for LD evaluation: they are not inflated in small samples, their definition encompasses multiallelic markers, and they can be computed with appreciable speed.

Published
2006
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