Integrating genome-wide association study and expression quantitative trait loci data identifies NEGR1 as a causal risk gene of major depression disorder

Background: Genome-wide association studies (GWAS) have identified several genetic variants associated with major depression disorder (MDD). However, pinpointing the causal variants which are responsible for the association signal at a risk locus remains a major challenge.

Methods: We used Summary data-based Mendelian Randomization (SMR) with Psychiatric Genomics Consortium (PGC) GWAS summary and brain expression quantitative trait loci (eQTL) data to identify genes whose expression levels are causally associated with MDD. Then we performed differential expression analysis, methylation quantitative trait loci analysis, and cognitive genetics analysis to investigate the potential roles of risk genes in the pathogenesis of MDD.

Results: Through SMR integrative analysis, we identified the SNP rs10789336 located in Neuronal growth regulator 1 (NEGR1) gene significantly affected the expression level of RPL31P12 in brain tissues and contributed to the risk of MDD (P = 1.96 × 10^-6). Consistently, the SNP rs10789336 was associated with the methylation levels of three nearby DNA methylation sites, including cg09256413 (NEGR1, P=1.72 × 10^-10), cg11418303 (prostaglandin E receptor 3 [PTGER3], P = 4.78 × 10^-6), and cg23032215 (ZRANB2 antisense RNA 2 [ZRANB2-AS2], P = 1.23 × 10^-4). Differential expression analysis suggested that the NEGR1 gene was upregulated in prefrontal cortex (P = 5.14 × 10^-3). Cognitive genetics analysis showed that the SNP rs10789336 was associated with cognitive performance (P = 2.41 × 10^-16), educational attainment (P = 1.75 × 10^-14), general cognitive function (P = 2.65 × 10^-12), and verbal numerical reasoning (P = 1.36 × 10^-12).

Conclusion: Collectively, our results revealed that the SNP rs10789336 in NEGR1 might confer risk to MDD. Further investigation of the roles of NEGR1 in the pathogenesis of MDD is warranted.