Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia

Anna C. Need, Joseph Patrick McEvoy, Massimo Gennarelli, Erin L. Heinzen, Dongliang Ge, Jessica M. Maia, Kevin V. Shianna, Min He, Elizabeth T. Cirulli, Curtis E. Gumbs, Qian Zhao, C. Ryan Campbell, Linda Hong, Peter B. Rosenquist, Anu Putkonen, Tero Hallikainen, Eila Repo-Tiihonen, Jari Tiihonen, Deborah L. Levy, Herbert Y. Meltzer & 1 others David B. Goldstein

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)303-312
Number of pages10
JournalAmerican Journal of Human Genetics
Volume91
Issue number2
DOIs
StatePublished - Aug 10 2012
Externally publishedYes

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Exome
Schizophrenia
Genome-Wide Association Study
Psychotic Disorders
Sample Size
Genes
Psychiatry
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. / Need, Anna C.; McEvoy, Joseph Patrick; Gennarelli, Massimo; Heinzen, Erin L.; Ge, Dongliang; Maia, Jessica M.; Shianna, Kevin V.; He, Min; Cirulli, Elizabeth T.; Gumbs, Curtis E.; Zhao, Qian; Campbell, C. Ryan; Hong, Linda; Rosenquist, Peter B.; Putkonen, Anu; Hallikainen, Tero; Repo-Tiihonen, Eila; Tiihonen, Jari; Levy, Deborah L.; Meltzer, Herbert Y.; Goldstein, David B.

In: American Journal of Human Genetics, Vol. 91, No. 2, 10.08.2012, p. 303-312.

Research output: Contribution to journalArticle

Need, AC, McEvoy, JP, Gennarelli, M, Heinzen, EL, Ge, D, Maia, JM, Shianna, KV, He, M, Cirulli, ET, Gumbs, CE, Zhao, Q, Campbell, CR, Hong, L, Rosenquist, PB, Putkonen, A, Hallikainen, T, Repo-Tiihonen, E, Tiihonen, J, Levy, DL, Meltzer, HY & Goldstein, DB 2012, 'Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia', American Journal of Human Genetics, vol. 91, no. 2, pp. 303-312. https://doi.org/10.1016/j.ajhg.2012.06.018
Need, Anna C. ; McEvoy, Joseph Patrick ; Gennarelli, Massimo ; Heinzen, Erin L. ; Ge, Dongliang ; Maia, Jessica M. ; Shianna, Kevin V. ; He, Min ; Cirulli, Elizabeth T. ; Gumbs, Curtis E. ; Zhao, Qian ; Campbell, C. Ryan ; Hong, Linda ; Rosenquist, Peter B. ; Putkonen, Anu ; Hallikainen, Tero ; Repo-Tiihonen, Eila ; Tiihonen, Jari ; Levy, Deborah L. ; Meltzer, Herbert Y. ; Goldstein, David B. / Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 2. pp. 303-312.
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AU - Heinzen, Erin L.

AU - Ge, Dongliang

AU - Maia, Jessica M.

AU - Shianna, Kevin V.

AU - He, Min

AU - Cirulli, Elizabeth T.

AU - Gumbs, Curtis E.

AU - Zhao, Qian

AU - Campbell, C. Ryan

AU - Hong, Linda

AU - Rosenquist, Peter B.

AU - Putkonen, Anu

AU - Hallikainen, Tero

AU - Repo-Tiihonen, Eila

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