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

Abstract

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.

Keywords: GWAS; family history; polygenic; schizophrenia.

FIG. 1

Manhattan plot of primary family history GWAS. Red and blue horizontal lines show thresholds for genome-wide (5 × 10⁻⁸) and suggestive (5 × 10⁻⁵) significance, respectively. Highlighted SNPs demonstrated specificity to a particular family history subgroup and were not within 1 Mb of any position attaining suggestive significance in the original schizophrenia analysis [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmgb].

FIG. 2

Predictive value of bipolar disorder, major depressive disorder, and schizophrenia polygene scores. Results based on varying SNP P-value inclusion thresholds are grouped by “training set.” Proportion of variance explained (Nagelkerke’s pseudo-R²) is shown on y-axis, and represents comparison of family history positive and negative cases. Displayed P-values correspond to the inclusion thresholds yielding the largest proportion of variance explained and are one-sided [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmgb].

FIG. 3

Estimated heritability of schizophrenia for family history positive and negative cases. SNP-heritability (SNP-h²) estimates based on genome-wide SNPs based on family history positive, family history negative and all schizophrenia cases, assuming disease prevalence of 1%; error bars represent standard error (S.E.) of estimate. Displayed P-value is one-sided [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmgb].