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

Publication ,  Journal Article
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 ...
Published in: Am J Hum Genet
August 10, 2012

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.

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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

August 10, 2012

Volume

91

Issue

2

Start / End Page

303 / 312

Location

United States

Related Subject Headings

  • United States
  • Sequence Analysis, DNA
  • Sequence Alignment
  • Schizophrenia
  • Risk Factors
  • Molecular Sequence Data
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetics & Heredity
 

Citation

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Need, A. C., McEvoy, J. P., Gennarelli, M., Heinzen, E. L., Ge, D., Maia, J. M., … Goldstein, D. B. (2012). Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet, 91(2), 303–312. https://doi.org/10.1016/j.ajhg.2012.06.018
Need, Anna C., Joseph P. McEvoy, Massimo Gennarelli, Erin L. Heinzen, Dongliang Ge, Jessica M. Maia, Kevin V. Shianna, et al. “Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.Am J Hum Genet 91, no. 2 (August 10, 2012): 303–12. https://doi.org/10.1016/j.ajhg.2012.06.018.
Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, Maia JM, et al. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet. 2012 Aug 10;91(2):303–12.
Need, Anna C., et al. “Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.Am J Hum Genet, vol. 91, no. 2, Aug. 2012, pp. 303–12. Pubmed, doi:10.1016/j.ajhg.2012.06.018.
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 P, Putkonen A, Hallikainen T, Repo-Tiihonen E, Tiihonen J, Levy DL, Meltzer HY, Goldstein DB. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet. 2012 Aug 10;91(2):303–312.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

August 10, 2012

Volume

91

Issue

2

Start / End Page

303 / 312

Location

United States

Related Subject Headings

  • United States
  • Sequence Analysis, DNA
  • Sequence Alignment
  • Schizophrenia
  • Risk Factors
  • Molecular Sequence Data
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetics & Heredity