Genome-wide association studies on Northern Italy isolated populations provide further support concerning genetic susceptibility for major depressive disorder

Major depressive disorder (MDD) is a psychiatric disorder with pathogenesis influenced by both genetic and environmental factors. To date, the molecular-level understanding of its aetiology remains unclear. Thus, we aimed to identify genetic variants and susceptibility genes for MDD with a genome-wide association study (GWAS) approach. We performed a meta-analysis of GWASs and a gene-based analysis on two Northern Italy isolated populations (cases/controls <i>n</i> = 166/472 and 33/320), followed by replication and polygenic risk score (PRS) analyses in Italian independent samples (cases <i>n</i> = 464, controls <i>n</i> = 339). We identified two novel MDD-associated genes, <i>KCNQ5</i> (lead SNP rs867262, <i>p</i> = 3.82 × 10⁻⁹) and <i>CTNNA2</i> (rs6729523, <i>p</i> = 1.25 × 10⁻⁸). The gene-based analysis revealed another six genes (<i>p</i> &lt; 2.703 × 10⁻⁶): <i>GRM7</i>, <i>CTNT4</i>, <i>SNRK</i>, <i>SRGAP3</i>, <i>TRAPPC9</i>, and <i>FHIT</i>. No replication of the genome-wide significant SNPs was found in the independent cohort, even if 14 SNPs around <i>CTNNA2</i> showed association with MDD and related phenotypes at the nominal level of <i>p</i> (&lt;0.05). Furthermore, the PRS model developed in the discovery cohort discriminated cases and controls in the replication cohort. Our work suggests new possible genes associated with MDD, and the PRS analysis confirms the polygenic nature of this disorder. Future studies are required to better understand the role of these findings in MDD.

重度抑郁症（Major depressive disorder, MDD）是一种发病机制受遗传与环境因素共同影响的精神疾病。截至目前，学界对其病因学的分子层面认知仍不明确。为此，本研究旨在通过全基因组关联研究（genome-wide association study, GWAS）方法，鉴定MDD的遗传变异与易感基因。我们对两组意大利北部孤立人群（病例/对照例数分别为166/472、33/320）的GWAS数据开展荟萃分析与基于基因的分析，随后在意大利独立样本队列（病例例数464，对照例数339）中进行验证分析与多基因风险评分（polygenic risk score, PRS）分析。本研究鉴定出两个与MDD显著相关的新基因：KCNQ5（领先单核苷酸多态性（single nucleotide polymorphism, SNP）rs867262，P=3.82×10⁻⁹）与CTNNA2（领先SNP rs6729523，P=1.25×10⁻⁸）。基于基因的分析还揭示了另外6个P值小于2.703×10⁻⁶的基因：GRM7、CTNT4、SNRK、SRGAP3、TRAPPC9与FHIT。尽管CTNNA2周边的14个SNP在名义P值阈值（P<0.05）下显示出与MDD及相关表型的关联，但在独立队列中未发现全基因组显著SNP的验证结果。此外，基于发现队列构建的PRS模型可在验证队列中区分病例与对照样本。本研究提出了若干与MDD相关的潜在新基因，而PRS分析证实了该疾病的多基因遗传本质。未来仍需开展进一步研究，以明确上述发现在MDD发病机制中的具体作用。