Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. Using self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of over 300,000 participants from UK Biobank (32,222 maternal cases, 16,613 paternal cases) and meta-analysing with published consortium data (n=74,046 with 25,580 cases across the discovery and replication analyses), six new AD-associated loci (P<5x10−8) are identified. Three contain genes relevant for AD and neurodegeneration: ADAM10, ADAMTS4, and ACE. Suggestive loci include drug targets such as VKORC1 (warfarin dose) and BZRAP1 (benzodiazepine receptor). We report evidence that association of SNPs and AD at the PVR gene is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, given that many are existing drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.
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