Autoimmune thyroid disease (AITD) and major depressive disorder (MDD) are common genetic diseases. The comorbidity of AITD and MDD has been widely demonstrated by large amounts of epidemiological studies. However, the genetic architectures of the comorbidity remain unknown.

We use large-scale GWAS summary data and novel genetic statistical methods to assess the genetic correlation and potential causality between AITD and MDD disorders. We perform cross-trait GWAS meta-analyses to identify genetic risk variants not previously associated with the individual traits. And we use summary-data-based mendelian randomisation to identify putative functional genes shared between diseases.

Both global and local genetic correlation study confirmed the genetic correlation of AITD and MDD. Through multi-trait analysis of GWAS (MTAG), we identified 112 SNPs associated with the conjoint phenotype, but not with individual traits. Mendelian randomisation confirmed the causal relationship between MDD (exposure) and AITD (outcome). The summary-based mendelian randomisation study found two plausible functional genes for AITD and MDD comorbidity.

AITD and MDD are genetically correlated in global and local chromosomal regions. MR analyses support a putative casual effect of MDD on AITD risk, though residual pleiotropy or confounding cannot be fully excluded. These findings highlight the need for triangulation with experimental and longitudinal studies to confirm causality.