NRXN1和CNTN6基因中的罕见拷贝数变异增加抽动秽语综合征风险。
Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome.
作者信息
Huang Alden Y, Yu Dongmei, Davis Lea K, Sul Jae Hoon, Tsetsos Fotis, Ramensky Vasily, Zelaya Ivette, Ramos Eliana Marisa, Osiecki Lisa, Chen Jason A, McGrath Lauren M, Illmann Cornelia, Sandor Paul, Barr Cathy L, Grados Marco, Singer Harvey S, Nöthen Markus M, Hebebrand Johannes, King Robert A, Dion Yves, Rouleau Guy, Budman Cathy L, Depienne Christel, Worbe Yulia, Hartmann Andreas, Müller-Vahl Kirsten R, Stuhrmann Manfred, Aschauer Harald, Stamenkovic Mara, Schloegelhofer Monika, Konstantinidis Anastasios, Lyon Gholson J, McMahon William M, Barta Csaba, Tarnok Zsanett, Nagy Peter, Batterson James R, Rizzo Renata, Cath Danielle C, Wolanczyk Tomasz, Berlin Cheston, Malaty Irene A, Okun Michael S, Woods Douglas W, Rees Elliott, Pato Carlos N, Pato Michele T, Knowles James A, Posthuma Danielle, Pauls David L, Cox Nancy J, Neale Benjamin M, Freimer Nelson B, Paschou Peristera, Mathews Carol A, Scharf Jeremiah M, Coppola Giovanni
机构信息
Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
出版信息
Neuron. 2017 Jun 21;94(6):1101-1111.e7. doi: 10.1016/j.neuron.2017.06.010.
Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.
抽动秽语综合征（TS）是一种典型的神经精神障碍，被认为是由皮质-纹状体-丘脑-皮质回路的异常发育和/或维持引起的。TS具有高度遗传性，但其潜在的遗传原因仍不明确，迄今为止尚未发现全基因组范围内具有显著意义的基因座。我们使用单核苷酸多态性（SNP）微阵列数据，对2434例TS病例和4093例血统匹配的对照组成的欧洲血统样本进行了罕见（频率<1%）拷贝数变异（CNV）分析。我们观察到总体CNV负担增加，这在大型（>1 Mb）、单例事件（优势比[OR]=2.28，95%置信区间[CI][1.39 - 3.79]，p = 1.2×10）和已知的致病性CNV中尤为突出（OR = 3.03[1.85 - 5.07]，p = 1.5×10）。我们还确定了两个全基因组范围内具有显著意义的基因座，每个基因座都使TS风险大幅增加（NRXN1缺失，OR = 20.3，95% CI[2.6 - 156.2]；CNTN6重复，OR = 10.1，95% CI[2.3 - 45.4]）。约1%的TS病例携带这些CNV中的一种，这表明罕见的结构变异对TS的遗传结构有显著贡献。
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