9619例抽动障碍病例的全基因组关联研究荟萃分析
Genome-Wide Association Study Meta-Analysis of 9619 Cases With Tic Disorders.
作者信息
Strom Nora I, Halvorsen Matthew W, Grove Jakob, Ásbjörnsdóttir Bergrún, Luðvígsson Pétur, Thorarensen Ólafur, de Schipper Elles, Bäckmann Julia, Andrén Per, Tian Chao, Als Thomas Damm, Nissen Judith Becker, Meier Sandra M, Bybjerg-Grauholm Jonas, Hougaard David M, Werge Thomas, Børglum Anders D, Hinds David A, Rück Christian, Mataix-Cols David, Stefánsson Hreinn, Stefansson Kari, Crowley James J, Mattheisen Manuel
机构信息
Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Region Stockholm, Sweden; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
出版信息
Biol Psychiatry. 2025 Apr 1;97(7):743-752. doi: 10.1016/j.biopsych.2024.07.025. Epub 2024 Oct 9.
BACKGROUND
Despite the significant personal and societal burden of tic disorders (TDs), treatment outcomes remain modest, necessitating a deeper understanding of their etiology. Family history is the biggest known risk factor, and identifying risk genes could accelerate progress in the field.
METHODS
Expanding upon previous sample size limitations, we added 4800 new TD cases and 971,560 controls and conducted a genome-wide association study (GWAS) meta-analysis with 9619 cases and 981,048 controls of European ancestry. We attempted to replicate the results in an independent deCODE genetics GWAS (885 TD cases and 310,367 controls). To characterize GWAS findings, we conducted several post-GWAS gene-based and enrichment analyses.
RESULTS
A genome-wide significant hit (rs79244681, p = 2.27 × 10) within MCHR2-AS1 was identified, although it was not replicated. Post-GWAS analyses revealed a 13.8% single nucleotide polymorphism heritability and 3 significant genes: BCL11B, NDFIP2, and RBM26. Common variant risk for TD was enriched within genes preferentially expressed in the cortico-striato-thalamo-cortical circuit (including the putamen, caudate, nucleus accumbens, and Brodmann area 9) and 5 brain cell types (excitatory and inhibitory telencephalon neurons, inhibitory diencephalon and mesencephalon neurons, and hindbrain and medium spiny neurons). TD polygenic risk was enriched within loss-of-function intolerant genes (p = .0017) and high-confidence neurodevelopmental disorder genes (p = .0108). Of 112 genetic correlations, 43 were statistically significant, showing high positive correlations with most psychiatric disorders. Of the 2 single nucleotide polymorphisms previously associated with TDs, one (rs2453763) replicated in an independent subsample of our GWAS (p = .00018).
CONCLUSIONS
This GWAS was still underpowered to identify high-confidence, replicable loci, but the results suggest imminent discovery of common genetic variants for TDs.
背景
尽管抽动障碍（TDs）给个人和社会带来了巨大负担，但治疗效果仍然有限，因此有必要更深入地了解其病因。家族病史是已知的最大风险因素，识别风险基因可以加速该领域的研究进展。
方法
在克服先前样本量限制的基础上，我们新增了4800例TD病例和971,560例对照，并对9619例欧洲血统的病例和981,048例对照进行了全基因组关联研究（GWAS）荟萃分析。我们试图在一项独立的deCODE遗传学GWAS（885例TD病例和310,367例对照）中重复这些结果。为了描述GWAS的发现，我们进行了多项GWAS后基于基因的分析和富集分析。
结果
在MCHR2-AS1内鉴定出一个全基因组显著位点（rs79244681，p = 2.27 × 10），尽管未得到重复验证。GWAS后分析显示单核苷酸多态性遗传率为13.8%，并发现了3个显著基因：BCL11B、NDFIP2和RBM26。TD的常见变异风险在皮质-纹状体-丘脑-皮质回路（包括壳核、尾状核、伏隔核和布罗德曼9区）中优先表达的基因以及5种脑细胞类型（兴奋性和抑制性端脑神经元、抑制性间脑和中脑神经元以及后脑和中等棘状神经元）中富集。TD多基因风险在功能丧失不耐受基因（p = .0017）和高置信度神经发育障碍基因（p = .0108）中富集。在112种遗传相关性中，43种具有统计学意义，与大多数精神疾病呈高度正相关。在先前与TD相关的2个单核苷酸多态性中，有一个（rs2453763）在我们GWAS的一个独立子样本中得到了重复验证（p = .00018）。
结论
这项GWAS仍缺乏足够的效力来识别高置信度、可重复的基因座，但结果表明即将发现TD的常见遗传变异。
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