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.
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA. anna.need@duke.edu
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.forename: Joseph P
authors.initials: JP
authors.lastname: McEvoy
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Maia
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Cirulli
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Gumbs
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Campbell
authors.forename: Linda
authors.initials: L
authors.lastname: Hong
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenquist
authors.forename: Anu
authors.initials: A
authors.lastname: Putkonen
authors.forename: Tero
authors.initials: T
authors.lastname: Hallikainen
authors.forename: Eila
authors.initials: E
authors.lastname: Repo-Tiihonen
authors.forename: Jari
authors.initials: J
authors.lastname: Tiihonen
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Levy
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D001483:Base Sequence; D059472:Exome / Q000235:genetics*; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014481:United States