TY - JOUR

T1 - Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

AU - Bigdeli, Tim B

AU - Ripke, Stephan

AU - Bacanu, Silviu-Alin

AU - Lee, Sang Hong

AU - Wray, Naomi R

AU - Gejman, Pablo V

AU - Rietschel, Marcella

AU - Cichon, Sven

AU - St Clair, David

AU - Corvin, Aiden

AU - Kirov, George

AU - McQuillin, Andrew

AU - Gurling, Hugh

AU - Rujescu, Dan

AU - Andreassen, Ole A

AU - Werge, Thomas

AU - Blackwood, Douglas H R

AU - Pato, Carlos N

AU - Pato, Michele T

AU - Malhotra, Anil K

AU - O'Donovan, Michael C

AU - Kendler, Kenneth S

AU - Fanous, Ayman H

AU - Knight, Jo

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

N1 - © 2015 Wiley Periodicals, Inc.

PY - 2016/3

Y1 - 2016/3

N2 - Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

AB - Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold <0.4). Estimates of variability in disease liability attributable to the aggregate effect of genome-wide SNPs were significantly greater for family history positive compared to family history negative cases (0.32 and 0.22, respectively; P = 0.031). We found suggestive evidence of allelic effects detectable in large GWAS of schizophrenia that might be specific to particular family history subgroups. However, consideration of a polygenic risk score indicated a significant enrichment among family history positive cases for common allelic effects. Familial illness might, therefore, represent a more heritable form of schizophrenia, as suggested by previous epidemiological studies.

KW - Bipolar Disorder

KW - Case-Control Studies

KW - Depressive Disorder, Major

KW - Family

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Inheritance Patterns

KW - Models, Genetic

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Schizophrenia

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1002/ajmg.b.32402

DO - 10.1002/ajmg.b.32402

M3 - Journal article

C2 - 26663532

VL - 171B

SP - 276

EP - 289

JO - American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

SN - 1552-4841

IS - 2

ER -