doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Major depression (MD) is a complex, heterogeneous neuropsychiatric disorder. An early age at onset of major depression (AAO-MD) has been associated with more severe illness, psychosis, and suicidality. However, not much is known about what contributes to individual variation in this important clinical characteristic. This study sought to investigate the genetic components underlying AAO-MD. To investigate the genetics of AAO-MD, we conducted a genome-wide association meta-analysis of AAO-MD based on self-reported age of symptoms onset and self-reported age at first diagnosis from the UK Biobank cohort (total N = 94,154). We examined the genetic relationship between AAO-MD and five other psychiatric disorders. Polygenic risk scores were derived to examine their association with five psychiatric outcomes and AAO-MD in independent sub-samples. We found a small but significant SNP-heritability (~6%) for the AAO-MD phenotype. No SNP or gene reached SNP or gene-level significance. We found evidence that AAO-MD has genetic overlap with MD risk ($$r_g$$ r g  = −0.49). Similarly, we found shared genetic risks between AAO-MD and autism-spectrum disorder, schizophrenia, bipolar disorder, and anorexia nervosa ($$r_g$$ r g range: −0.3 to −0.5). Polygenic risk scores for AAO-MD were associated with MD, schizophrenia, and bipolar disorder, and AAO-MD was in turn associated with polygenic risk scores derived from these disorders. Overall, our results indicate that AAO-MD is heritable, and there is an inverse genetic relationship between AAO-MD and both major depression and other psychiatric disorders, meaning that SNPs associated with earlier age at onset tend to increase the risk for psychiatric disorders. These findings suggest that the genetics of AAO-MD contribute to the shared genetic architecture observed between psychiatric disorders.

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Despite increasing therapeutic options to treat rheumatoid arthritis (RA), many patients fail to reach treatment targets. The use of antidiabetic drugs like thiazolidinediones has been associated with lower RA risk. We aimed to explore the repurposing potential of antidiabetic drugs in RA prevention by assessing associations between genetic variation in antidiabetic drug target genes and RA using Mendelian randomization (MR). A two-sample MR design was used to estimate the association between the antidiabetic drug and RA risk using summary statistics from genome-wide association studies (GWAS). We selected independent genetic variants from the gene(s) that encode the target protein(s) of the investigated antidiabetic drug as instruments. We extracted the associations of instruments with blood glucose concentration and RA from the UK Biobank and a GWAS meta-analysis of clinically diagnosed RA, respectively. The effect of genetic variation in the drug target(s) on RA risk was estimated by the Wald ratio test or inverse-variance weighted method. Insulin and its analogues, thiazolidinediones, and sulfonylureas had valid genetic instruments (n = 1, 1, and 2, respectively). Genetic variation in thiazolidinedione target (gene: PPARG) was inversely associated with RA risk (odds ratio [OR] 0.38 per 0.1mmol/L glucose lowering, 95% confidence interval [CI] 0.20–0.73). Corresponding ORs (95%CIs) were 0.83 (0.44–1.55) for genetic variation in the targets of insulin and its analogues (gene: INSR), and 1.12 (0.83, 1.49) 1.25 (0.78-2.00) for genetic variation in the sulfonylurea targets (gene: ABCC8 and KCNJ11). In conclusion, genetic variation in the thiazolidinedione target is associated with a lower RA risk. The underlying mechanisms warrant further exploration.

Background Major depression (MD) is a heterogeneous disorder; however, the extent to which genetic factors distinguish MD patient subgroups (genetic heterogeneity) remains uncertain. This study sought evidence for genetic heterogeneity in MD. Methods Using UK Biobank cohort, the authors defined 16 MD subtypes within eight comparison groups (vegetative symptoms, symptom severity, comorbid anxiety disorder, age at onset, recurrence, suicidality, impairment and postpartum depression; N~3,000-47,000). To compare genetic architecture of these subtypes, subtype-specific genome-wide association studies were performed to estimate SNP-heritability, and genetic correlations within subtype comparison and with other related disorders or traits. Results MD subtypes were divergent in their SNP-heritability, and genetic correlations both within subtype comparisons and with other related disorders/traits. Three subtype comparisons (age at onset, suicidality, and impairment) showed significant differences in SNP-heritability; while genetic correlations within subtypes comparisons ranged from 0.55 to 0.86, suggesting genetic profiles are only partially shared among MD subtypes. Furthermore, subtypes that are more clinically challenging, e.g., early-onset, recurrent, suicidal, more severely impaired, had stronger genetic correlations with other psychiatric disorders. MD with atypical features showed a positive genetic correlation (+0.40) with BMI while a negative correlation (-0.09) was found in those with non-atypical symptoms. Novel genomic loci with subtype-specific effects were identified. Conclusions These results provide the most comprehensive evidence to date for genetic heterogeneity within MD, and suggest that the phenotypic complexity of MD can be effectively reduced by studying the subtypes which share partially distinct etiologies.