Association of rare PTP4A1-PHF3-EYS variants with alcohol dependence

In a recent genome-wide association study (GWAS), we identified a unique novel, functional and replicable risk genomic region for alcohol dependence. This region (Chr6: 64,066,604-64,831,120) included the protein tyrosine phosphatase type IVA 1 gene (PTP4A1), the plant homeodomain finger protein 3 gene (PHF3) and part of the eyes shut homolog gene (EYS). It was enriched with numerous replicable common risk variants (minor allele frequency (MAF) >0.05) for alcohol dependence across African–Americans, European–Americans and European–Australians. Within 90 Mb range surrounding this region in the discovery sample, all variants with P<10⁻⁴ were concentrated in this region. Most of these risk variants had significant cis-acting regulatory effects on mRNA expression. The distributions of −log(P) values for association and functional signals in this region were highly consistent across six independent populations. We thus speculated that this region might harbor a causal variant(s) for alcohol dependence.¹

Rare variants, which may not be well-captured by a GWAS, may be of equal importance as common variants in the etiology of complex disorders. Recent studies have indicated that rare variants, which usually have strong effects and high penetrance, are involved in the genetic susceptibility to an increasing number of human diseases or traits; for example, plasma levels of high-density lipoprotein cholesterol² and type 1 diabetes³ as well complex neuropsychiatric disorders such as autism.^{4, 5, 6} However, the associations between rare variants within the PTP4A1-PHF3-EYS region and alcohol dependence have never been tested. Furthermore, alcohol dependence has high rates of comorbidity with numerous neuropsychiatric disorders, including anxiety disorders, major depression, bipolar disorders, schizophrenia, post-traumatic stress disorder and so on. The associations between rare PTP4A1-PHF3-EYS variants and these neuropsychiatric disorders have never been tested either.

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