Abstract
BACKGROUND: Little is known regarding the shared genetic architecture underlying the phenotypic associations between depression and preterm birth (PTB). We aim to investigate the genetic overlap and causality of depression with PTB. METHODS: Leveraging summary statistics from the largest genome-wide association studies for broad depression (N(total) = 807,533), major depression (N(total) = 173,005), bipolar disorder (N(total) = 414,466), and PTB (N(total) = 226,330), we conducted a large-scale genome-wide cross-trait analysis to assess global and local genetic correlations, identify pleiotropic loci, and infer potential causal relationships. RESULTS: Positive genetic correlations were observed between PTB and broad depression (r(g) = 0.242), major depression (r(g) = 0.236), and bipolar disorder (r(g) = 0.133) using the linkage disequilibrium score regression, which were further verified by the genetic covariance analyzer. Local genetic correlation was identified at chromosome 11q22.3 (harbors NCAM1-TTC12-ANKK1-DRD2) for PTB with depression. Cross-trait meta-analysis identified two loci shared between PTB and broad depression, two loci shared with major depression, and five loci shared with bipolar disorder, among which three were novel (rs7813444, rs3132948 and rs9273363). Mendelian randomization demonstrated a significantly increased risk of PTB for genetic liability to broad depression (odds ratio [OR]=1.30; 95% confidence interval [CI]: 1.11-1.52) and major depression (OR=1.27; 95%CI: 1.08-1.49), and the estimates remained significant across the sensitivity analyses. CONCLUSIONS: Our findings demonstrate an intrinsic link underlying depression and PTB and shed novel light on the biological mechanisms, highlighting an important role of early screening and effective intervention of depression in PTB prevention, and may provide novel treatment strategies for both diseases.