@article{e3ba16cf451e4eb7ae7b6f3d815b0f2c,
title = "Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia",
abstract = "Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.",
author = "Need, {Anna C.} and McEvoy, {Joseph P.} and Massimo Gennarelli and Heinzen, {Erin L.} and Dongliang Ge and Maia, {Jessica M.} and Shianna, {Kevin V.} and Min He and Cirulli, {Elizabeth T.} and Gumbs, {Curtis E.} and Qian Zhao and Campbell, {C. Ryan} and Linda Hong and Peter Rosenquist and Anu Putkonen and Tero Hallikainen and Eila Repo-Tiihonen and Jari Tiihonen and Levy, {Deborah L.} and Meltzer, {Herbert Y.} and Goldstein, {David B.}",
note = "Funding Information: We thank the participants who made their DNA available for research. We thank Jordan Silver and Marlyne Silver; doctors and staff at Central Regional Hospital; Robert Millet, Edward Leuth, and other doctors and staff at Carolina Behavioral Care for local patient recruitment; and Latasha Little, Ken Cronin, Melora McCall, and Alex McKenzie for lab support. For the Italian cohort, we acknowledge Catia Scassellati and Cristian Bonvicini for sample handling and Stefano Bignotti, Giuseppe Rossi, and Alessandra Minelli for recruitment. We thank the Murdock study community registry and biorepository pro00011196, D. Daskalakis, R. Brown, A. Holden, E. Behr, W. Lowe, P. Lugar, J. Milner, K. Welsh-Bohmer, D. Valle, J. Hoover-Fong, D. Marchuk, S. Palmer, E. Pras, D. Lancet, and Z. Farfel for control DNA. This work was funded by National Institute of Mental Health (NIMH) grant 3RC2MH089915-01W1 and R01 grant MH071523, National Institute of Neurological Disorders and Stroke grant RC2NS070344, National Institute of Allergy and Infectious Diseases grant UO1AIO67854, Italian Ministry of Health (Ricerca Corrente) and Associazione Fatebenefratelli per la Ricerca grants, Ellison Funding, National Institute on Aging P30 grant AG028377, the Sidney R. Baer, Jr. Foundation, the Essel Foundation, the Carmela and Menachem Abraham Fund, and the Brain and Behavior Research Foundation. This research was performed in collaboration with the International Serious Adverse Events Consortium, whose membership includes Abbott, Amgen, Astra-Zeneca, Cerner, Daiichi-Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda, and the Wellcome Trust. The NIMH Cell Repository at Rutgers University provided schizophrenia follow-up samples. H.Y.M. is a shareholder in SureGene, LLC. ",
year = "2012",
month = aug,
day = "10",
doi = "10.1016/j.ajhg.2012.06.018",
language = "English (US)",
volume = "91",
pages = "303--312",
journal = "American journal of human genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",
}