META-ANALYSIS OF RARE CNV GENOME-WIDE ASSOCIATION STUDIES ACROSS MAJOR PSYCHIATRIC DISORDERS IN EUR, AFR/AFAM, AND ASN/ASAM POPULATIONS

Abstract

Genome-wide association studies (GWAS) to date have been able to leverage large sample sizes to identify genomic loci that contribute to risk for various psychiatric disorders. However, GWAS of copy number variants (CNVs) have prioritized identifying risk loci within European populations due to the lack of power in diverse ancestry groups. In this study, we called CNVs in a diverse group of samples to create CNV datasets for 2 additional ancestry groups: African/African American (AFR/AFAM) and Asian/Asian American (ASN/ASAM). SNPweights was used to infer genome-wide genetic ancestry for each sample. We were then able to boost power at specific loci by using a meta-analysis to combine EUR, AFR/AFAM, and ASN/ASAM CNV analyses (N=571,803).

Rare copy number variants have been implicated in a cross-disorder European cohort (N=537,466) that includes major psychiatric disorders such as autism (ASD), schizophrenia (SCZ), major depressive disorder (MDD), bipolar disorder (BD), post-traumatic stress disorder (PTSD), and attention-deficit/hyperactivity disorder (ADHD). This analysis was able to identify novel loci with the statistical power that comes with being the largest CNV study to date. Naturally, the inclusion of diverse samples in this analysis can further lead to novel discoveries. Additional CNV-GWAS were performed for cross-disorder datasets in AFR/AFAM (N=17,474) and ASN/ASAM (N=16,863) populations. Meta-analysis of all 3 populations used an inverse-variance weighting to account for the disparity of sample size between populations. We compared EUR CNV-GWAS and burden results with those from the meta-analysis as these were the most well-powered tests. The effect was a substantial increase in significance levels at specific loci that reached testable CNV frequencies in the diverse groups. Comparing the EUR analysis with the trans-ancestry analysis allows us to quantify the contribution of the diverse groups and provide insight into the genomic loci associated with psychiatric disorders in AFR/AFAM and ASN/ASAM populations once similar sample sizes are reached. This study highlights the importance of expanding diversity during data collection so that the genotype-phenotype relationships can benefit people worldwide.