Sex‐Specific Association Between Polymorphisms in Estrogen Receptor Alpha Gene (ESR1) and Depression: A Genome‐Wide Association Study of All of Us and UK Biobank Data

Major depressive disorder (MDD) is prevalent worldwide, substantially and negatively impacting both the quality and length of life of 280 million people globally. The genetic risk factors of MDD have been studied in various previous research, but the findings lack consistency. Sex/gender and racial/ethnic disparities have been reported; however, many previous genetic studies, represented by large-scale genome-wide association studies (GWASs) are known to lack diversity in the study cohorts. All of Us is a biorepository aiming to focus on the historically underrepresented groups. We perform GWASs for the MDD phenotype, using over 200,000 participants' genotypes and carry out sex- and racial/ethnic-specific subgroup studies. We identified a risk locus (chr6:151945242) in Estrogen Receptor Alpha Gene (ESR1) (p = <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:mrow><mml:mrow><mml:mn>1.70</mml:mn> <mml:mo>×</mml:mo> <mml:msup><mml:mn>10</mml:mn> <mml:mrow><mml:mo>-</mml:mo> <mml:mn>9</mml:mn></mml:mrow> </mml:msup> </mml:mrow> </mml:mrow> <mml:annotation>$1.70\times {10}^{-9}$</mml:annotation></mml:semantics> </mml:math> ), and further confirmed the genetic association is sex-specific. The single-nucleotide polymorphism (SNP) chr6:151945242 was significant only in the male group, but not in the female group. These findings were replicated in the UK Biobank and echo with existing studies on the ESR1 gene and depressive disorders. Our results indicate that the All of Us program is a reliable resource for GWAS, as well as shedding light on further investigation of sex- and racial/ethnic-specific genome association, especially in underrepresented groups of the US population.