Szatkiewicz J P, O'Dushlaine C, Chen G, Chambert K, Moran J L, Neale B M, Fromer M, Ruderfer D, Akterin S, Bergen S E, Kähler A, Magnusson P K E, Kim Y, Crowley J J, Rees E, Kirov G, O'Donovan M C, Owen M J, Walters J, Scolnick E, Sklar P, Purcell S, Hultman C M, McCarroll S A, Sullivan P F
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mol Psychiatry. 2014 Jul;19(7):762-73. doi: 10.1038/mp.2014.40. Epub 2014 Apr 29.
Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.
精神分裂症（SCZ）是一种具有高度遗传性的神经精神疾病，其遗传病因复杂。先前的全基因组调查显示，SCZ病例中存在更大负担的大型罕见拷贝数变异（CNV），并鉴定出多个增加SCZ风险的罕见复发性CNV，尽管其外显率不完全且具有多效性。识别更多的复发性CNV以及富含SCZ的CNV的生物学途径需要更大的样本量。我们使用瑞典全国样本（4719例病例和5917例对照）对与SCZ相关的CNV进行了全基因组调查。利用基因分型阵列强度数据生成高可信度的CNV调用，并测量其对SCZ风险的影响。我们的数据证实了SCZ病例中大型罕见CNV负担的增加，以及复发性16p11.2重复、22q11.2缺失和3q29缺失的显著关联。我们报告了17q12重复的新关联（优势比=4.16，P=0.018），该重复先前与自闭症和智力迟钝有关，但与SCZ无关。有趣的是，基因集关联分析涉及先前通过常见变异和外显子测序与SCZ相关的生物学途径（钙通道信号传导和脆性X智力迟钝蛋白的结合伙伴）。我们发现，在突触后密度中的基因、通过SCZ全基因组关联研究涉及的基因组区域以及定位于线粒体和细胞质的基因产物中，最大CNV（>500 kb）的负担显著增加。我们的研究结果表明，多条基因组研究路线——全基因组CNV筛查、常见变异和外显子变异——正在汇聚到相似的途径和/或基因集上。
