背景:罕见变异被认为在精神障碍的遗传结构中起重要作用,特别是在编码区域。然而,有限的证据支持罕见变异对焦虑的影响.
方法:使用来自英国生物库200,643名参与者的全外显子组测序数据,我们调查了罕见变异对焦虑的影响.首先,我们利用基因型数据和来自焦虑障碍全基因组关联研究(GWAS)的汇总数据,计算了焦虑的遗传风险评分(GRS).随后,我们确定了最低50%GRS内的个体,一个亚组更可能携带致病性罕见变异。在这个子组中,我们将具有最高10%7项广泛性焦虑症量表(GAD-7)得分的个体分类为病例(N=1869),GAD-7得分最低的10%的人被指定为对照(N=1869)。最后,我们进行了基于基因的负荷试验和单变异关联分析,以评估罕见变异与焦虑之间的关系.
结果:完全,47,800个MAF≤0.01的变体被注释为非良性编码变体,由42,698个非同义SNV组成,489非移码替换,236移码替换,617个止损收益和40个止损变量。变异聚集后,在基于基因的关联分析中包括5066个基因。完全正确,在负荷试验中检测到11个候选基因,如RNF123(PBonferroni调整=3.40×10-6),MOAP1(PBonferroni调整=4.35×10-4),CCDC110(PBonferroni调整=5.83×10-4)。单变异测试检测到9个罕见变异,如rs35726701(RNF123)(PBonferroniadjusted=3.16×10-10)和rs16942615(CAMTA2)(PBonferroniadjusted=4.04×10-4)。值得注意的是,在两个测试中都鉴定了RNF123、CCDC110、DNAH2和CSKMT基因。
结论:我们的研究确定了蛋白质编码区焦虑的新候选基因,揭示罕见变异对焦虑的贡献。
BACKGROUND: Rare variants are believed to play a substantial role in the genetic architecture of mental disorders, particularly in coding regions. However, limited evidence supports the impact of rare variants on anxiety.
METHODS: Using whole-
exome sequencing data from 200,643 participants in the UK Biobank, we investigated the contribution of rare variants to anxiety. Firstly, we computed genetic risk score (GRS) of anxiety utilizing genotype data and summary data from a genome-wide association
study (GWAS) on anxiety disorder. Subsequently, we identified individuals within the lowest 50% GRS, a subgroup more likely to carry pathogenic rare variants. Within this subgroup, we classified individuals with the highest 10% 7-item Generalized Anxiety Disorder scale (GAD-7) score as cases (N = 1869), and those with the lowest 10% GAD-7 score were designated as controls (N = 1869). Finally, we conducted gene-based burden tests and single-variant association analyses to assess the relationship between rare variants and anxiety.
RESULTS: Totally, 47,800 variants with MAF ≤0.01 were annotated as non-benign coding variants, consisting of 42,698 nonsynonymous SNVs, 489 nonframeshift substitution, 236 frameshift substitution, 617 stop-gain and 40 stop-loss variants. After variation aggregation, 5066 genes were included in gene-based association analysis. Totally, 11 candidate genes were detected in burden test, such as RNF123 (PBonferroni adjusted = 3.40 × 10-6), MOAP1(PBonferroni adjusted = 4.35 × 10-4), CCDC110 (PBonferroni adjusted = 5.83 × 10-4). Single-variant test detected 9 rare variants, such as rs35726701(RNF123)(PBonferroni adjusted = 3.16 × 10-10) and rs16942615(CAMTA2) (PBonferroni adjusted = 4.04 × 10-4). Notably, RNF123, CCDC110, DNAH2, and CSKMT gene were identified in both tests.
CONCLUSIONS: Our
study identified novel candidate genes for anxiety in protein-coding regions, revealing the contribution of rare variants to anxiety.