Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

Abstract

Background: Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

Methods: We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.

Findings: SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.

Interpretation: Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.

Funding: National Institute of Mental Health.

Figure 1. Manhattan plot of primary fixed-effects meta-analysis

Horizontal line shows threshold for genome-wide significance (p<5×10⁻⁸).

Figure 2. Association results and forest plots showing effect size for genome-wide significant loci by disorder

Data in parentheses are numbers of cases or controls. Het_p=p value for the heterogeneity test. Het_I=heterogeneity test statistic. IQS=imputation quality score (INFO). ln(OR)=log of the odds ratio (OR). F=frequency. SE=standard error of the log OR. ADHD=attention deficit-hyperactivity disorder. ASD=autism spectrum disorders. BPD=bipolar disorder. MDD=major depressive disorder. *Number of studies in which the variant was directly genotyped.

Figure 3. Pair-wise cross-disorder polygene analysis

We derived polygene risk scores for each disorder (discovery sets) and applied them sequentially to the remaining disorders (target sets). Results are grouped by each discovery set. Each pair is shown on the x-axis and the proportion of variance explained for the target disorder (estimated via Nagelkerke’s pseudo R²) on the y-axis. For purposes of illustration, three p_T cutoffs are shown, but appendix p 62 shows the proportion of variance results for a broader range of cutoffs. p_T=training-set p value (used to select training set SNPs). Significance of results: a=p<0·05; b=p<10⁻⁴; c=p<10⁻⁸; d=p<10¹²; e=p<10⁻¹⁶; f=p<10⁻⁵⁰. ADHD=attention deficit-hyperactivity disorder. ASD=autism spectrum disorders. BPD=bipolar disorder. MDD=major depressive disorder.