Recurrent & non-recurrent copy number variants in Native Americans and a cosmopolitan sample in relation to Alcohol Use Disorder and other psychiatric diseases

Background Copy Number Variants (CNVs) can alter disease susceptibility by gene deletion, duplication and other mechanisms. CNVs are implicated in neuropsychiatric diseases. However, their rarity or de novo nature impedes linkage analysis. Therefore, we identified recurrent CNVs (rCNVs) in Native Americans with low genetic admixture and high prevalence of Alcohol Use Disorder (AUD) and other psychiatric disorders. Results Large (> 200 kb) rCNVs were abundant in PI and SWI, almost all carrying at least one rCNV, and with some CNVs found in both geographically and linguistically distinct tribes. In patients carrying rCNVs, gene deletions led to haploinsufficiency, and duplications overexpression. Haplotype analysis revealed a common chromosome 6p21.33 rCNV that persisted in Native Americans for at least 750 generations, leading to haploinsufficiency of at least two genes. Gene-based CNV burden did not predict AUD or other psychiatric disorders. However, an rCNV, found in PI and duplicating three genes within the 22q11.2 Velocardiofacial Syndrome region, may be associated with psychiatric disease. Among 27 heterozygotes, 22 had AUD (OR = 3.18 [1.18–8.59], p = 0.01), and 24 had a psychiatric diagnosis (OR = 4.8 [1.4–16], p = 0.006, FDR 0.07 adjusted for 13 common rCNVs tested). Conclusion Recurrent CNVs are prevalent in Native American populations and have ancient origins. While gene-based CNV burden did not predict AUD or other psychiatric disorders, specific rCNVs, such as those within 22q11.2 region, may confer higher risk for psychiatric conditions. Other less abundant rCNVs and non-recurrent CNVs might also alter risk, the effects of such CNVs being undetectable via genome-wide association studies with single SNPs.