Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed 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 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. 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 after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing sample sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated (P < 5 × 10⁻⁸) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent sample, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.

In this article, a meta-analysis of the significant variants in the UK Biobank sample with a previously published study by 23andMe was included. Due to the individual study results being reported on different scales, the meta-analytic point estimates were not reliable. We have re-analysed the 17 significant variants in the UK Biobank using a comparable approach to 23andMe in Plink. We present an updated version of Table 1 associated with this Addendum that includes the newly calculated comparable effect size estimates for UK Biobank, the updated meta-analysis results and we have extended the table legend to provide information on the updated columns. As a consequence of the new analysis, the original statement in the first paragraph under the subheading "Genome-wide association study of depression" reading "All 17 variants remained significant (P < 5 × 10-8) in the meta-analysis" should be amended to "10 variants remained significant (P < 5 × 10-8) in the meta-analysis". There was no change to the direction of allelic effect in either cohort.

Intramuscular fat content (IMF), one of the most important carcass traits in beef cattle, is controlled by complex regulatory factors. At present, molecular mechanisms involved in regulating IMF and fat metabolism in beef cattle are not well understood. Our objective was to integrate comparative transcriptomic and competing endogenous RNA (ceRNA) network analyses to identify candidate messenger RNAs (mRNAs) and regulatory RNAs involved in molecular regulation of longissimus dorsi muscle (LDM) tissue for IMF and fat metabolism of 5 beef cattle breeds (Angus, Chinese Simmental, Luxi, Nanyang, and Shandong Black). In total, 34 circRNAs, 57 lncRNAs, 15 miRNAs, and 374 mRNAs were identified by integrating gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Furthermore, 7 key subnets with 16 circRNAs, 43 lncRNAs, 7 miRNAs, and 237 mRNAs were detected through clustering analyses, whereas GO enrichment analysis of identified RNAs revealed 48, 13, and 28 significantly enriched GO terms related to IMF in biological process, molecular function, and cellular component categories, respectively. The main metabolic-signaling pathways associated with IMF and fat metabolism that were enriched included metabolic, calcium, cGMP-PKG, thyroid hormone, and oxytocin signaling pathways. Moreover, MCU, CYB5R1, and BAG3 genes were common among the 10 comparative groups defined as important candidate marker genes for fat metabolism in beef cattle. Contributions of transcriptome profiles from various beef breeds and a competing endogenous RNA (ceRNA) regulatory network underlying phenotypic differences in IMF provided novel insights into molecular mechanisms associated with meat quality.

Major depressive disorder (MDD) is the second largest cause of global disease burden. It has an estimated heritability of 37%, but published genome-wide association studies have so far identified few risk loci. Haplotype-block-based regional heritability mapping (HRHM) estimates the localized genetic variance explained by common variants within haplotype blocks, integrating the effects of multiple variants, and may be more powerful for identifying MDD-associated genomic regions. We applied HRHM to Generation Scotland: The Scottish Family Health Study, a large family- and population-based Scottish cohort (N = 19,896). Single-single nucleotide polymorphism (SNP) and haplotype-based association tests were used to localize the association signal within the regions identified by HRHM. Functional prediction was used to investigate the effect of MDD-associated SNPs within the regions. A haplotype block across a 24-kb region within the TOX2 gene reached genome-wide significance in HRHM. Single-SNP- and haplotype-based association tests demonstrated that five of nine genotyped SNPs and two haplotypes within this block were significantly associated with MDD. The expression of TOX2 and a brain-specific long noncoding RNA RP1-269M15.3 in frontal cortex and nucleus accumbens basal ganglia, respectively, were significantly regulated by MDD-associated SNPs within this region. Both the regional heritability and single-SNP associations within this block were replicated in the UK-Ireland group of the most recent release of the Psychiatric Genomics Consortium (PGC), the PGC2-MDD (Major Depression Dataset). The SNP association was also replicated in a depressive symptom sample that shares some individuals with the PGC2-MDD. This study highlights the value of HRHM for MDD and provides an important target within TOX2 for further functional studies.