Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia.
Sci Rep. 2021 Jan 28;11(1):2484. doi: 10.1038/s41598-021-82123-5.
Neuroticism is a personality trait, which is an important risk factor for psychiatric disorders. Recent genome-wide studies reported about 600 genes potentially influencing neuroticism. Little is known about the mechanisms of their action. Here, we aimed to conduct a more detailed analysis of genes that can regulate the level of neuroticism. Using UK Biobank-based GWAS summary statistics, we performed a gene-based association analysis using four sets of within-gene variants, each set possessing specific protein-coding properties. To guard against the influence of strong GWAS signals outside the gene, we used a specially designed procedure called "polygene pruning". As a result, we identified 190 genes associated with neuroticism due to the effect of within-gene variants rather than strong GWAS signals outside the gene. Thirty eight of these genes are new. Within all genes identified, we distinguished two slightly overlapping groups obtained from using protein-coding and non-coding variants. Many genes in the former group included potentially pathogenic variants. For some genes in the latter group, we found evidence of pleiotropy with gene expression. Using a bioinformatics analysis, we prioritized the neuroticism genes and showed that the genes that contribute to neuroticism through their within-gene variants are the most appropriate candidate genes.
神经质是一种人格特质，是精神障碍的重要危险因素。最近的全基因组研究报告了大约 600 个可能影响神经质的基因。它们作用的机制知之甚少。在这里，我们旨在对可以调节神经质水平的基因进行更详细的分析。使用基于英国生物库的 GWAS 汇总统计数据，我们使用四组基因内变体进行了基于基因的关联分析，每组变体都具有特定的蛋白质编码特性。为了防止基因外强 GWAS 信号的影响，我们使用了一种名为“多基因修剪”的专门设计的程序。结果，我们确定了 190 个由于基因内变体而不是基因外强 GWAS 信号而与神经质相关的基因。其中 38 个是新的。在所有鉴定的基因中，我们区分了两个略微重叠的组，这两个组是使用编码蛋白和非编码变体获得的。前者组中的许多基因包含潜在的致病变体。对于后者组中的一些基因，我们发现了与基因表达的多效性有关的证据。通过生物信息学分析，我们对神经质基因进行了优先级排序，并表明通过基因内变体导致神经质的基因是最合适的候选基因。
