POLYGENIC DISSECTION OF T2DM AND DEPRESSIVE SYMPTOMS

The association between Type 2 Diabetes (T2DM) and depression has been consistently reported in epidemiological studies. The T2DM-depression link may be symptom-specific. We therefore examined whether polygenic risk scores for T2DM predict specific depressive symptoms in the Psychiatric Genomics Consortium Major Depressive Disorder Phase 2 (PGC-MDD-29) dataset. T2DM-polygenic scores were constructed from the association summary statistics of Diabetes Genetic Replication And Meta-analysis Consortium (DIAGRAM; 12,171 cases and 56,862 controls) at association p-value threshold of 0.5 (PT<0. 0.5). Stepwise regression was used to test for association between T2DM-polygenic scores at PT<0.5 and nine specific depressive symptoms in PGC-MDD-29 dataset, adjusting for ancestry principal components and study. The four cohorts from PGC-MDD-29 dataset included in this study were: i) CoFaMS, ii) PsyCoLaus, iii) NESDA/NTR and iv) SHP0. The combined data consists of 6542 participants of European ancestry, with 2,360 cases of depression and 4,182 controls. Feelings of guilt/worthlessness is the only significant depressive symptom predictor for T2DM-polygenic scores (β=-0.0041; p=0.0037). It is present in 1,771 (75%) cases and 120 (3%) controls. This effect came primarily from depression cases (β=-0.0058; p=0.0002), with limited information from controls (β=-0.0003; p=0.7903). This study provides the first evidence of a shared genetic aetiology between T2DM and feelings of guilt/worthlessness, particularly in people with depression. No association was found between T2DM-polygenic scores and depressive symptoms which are more related to T2DM, such as changes in appetite/weight. Previous studies have reported an association between appetite/weight and inflammatory markers but not with glucose-related measures. Longitudinal prospective studies examining the association between specific symptoms of T2DM and depression are needed to clarify the underlying mechanism.