Genome-wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis-regulation of BORCS7, AS3MT, and NT5C2 in the human brain.
Genome-wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis-regulation of BORCS7, AS3MT, and NT5C2 in the human brain.
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DOI：
10.1002/ajmg.b.32445
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发表时间：
2016-09
期刊：
影响因子：
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通讯作者：
Bray NJ
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作者：
Duarte RRR;Troakes C;Nolan M;Srivastava DP;Murray RM;Bray NJ
染色体10q24.32-q24.33是精神分裂症全基因组关联研究中最有说服力的危险基因座之一。然而，广泛的连锁不平衡使得在该基因座上很难区分实际的易感基因(S)，限制了其在改善对该病的生物学理解方面的价值。在缺乏能够解释这种关联的编码变化的情况下，风险很可能是由于该区域中一个或多个基因的调节发生变化而产生的。因此，我们使用高度敏感的等位基因特异性表达方法来评估两个最受支持的精神分裂症风险变量(SNP rs11191419和Indel CH10_104957618_I/rs202213518)对人脑中主要位置候选BORCS7、AS3MT、CNNM2和NT5C2的顺式调节效应。Rs11191419的杂合性与BORCS7和AS3MT在胎儿和成人脑中的等位基因表达增加以及NT5C2在成人脑中的等位基因表达减少相关。在胎儿和成人脑中，CH10_104957618_I杂合子与NT5C2等位基因表达降低有关。比较杂合子和纯合子中危险等位基因的cDNA率，结果表明，对成人前额叶背外侧皮质NT5C2表达的顺式影响在很大程度上是由这两个危险变异的基因决定的。虽然不排除对该区域其他基因的影响，但这项研究表明，BORCS7、AS3MT和NT5C2的神经表达变化与精神分裂症的易感性有关，这些易感性源于染色体10q24基因座的遗传变异。©2016作者。《美国医学遗传学杂志B：神经精神病学遗传学》，由Wiley期刊出版公司出版。
Chromosome 10q24.32‐q24.33 is one of the most robustly supported risk loci to emerge from genome‐wide association studies (GWAS) of schizophrenia. However, extensive linkage disequilibrium makes it difficult to distinguish the actual susceptibility gene(s) at the locus, limiting its value for improving biological understanding of the condition. In the absence of coding changes that can account for the association, risk is likely conferred by altered regulation of one or more genes in the region. We, therefore, used highly sensitive measures of allele‐specific expression to assess cis‐regulatory effects associated with the two best‐supported schizophrenia risk variants (SNP rs11191419 and indel ch10_104957618_I/rs202213518) on the primary positional candidates BORCS7, AS3MT, CNNM2, and NT5C2 in the human brain. Heterozygosity at rs11191419 was associated with increased allelic expression of BORCS7 and AS3MT in the fetal and adult brain, and with reduced allelic expression of NT5C2 in the adult brain. Heterozygosity at ch10_104957618_I was associated with reduced allelic expression of NT5C2 in both the fetal and adult brain. Comparisons between cDNA ratios in heterozygotes and homozygotes for the risk alleles indicated that cis‐effects on NT5C2 expression in the adult dorsolateral prefrontal cortex could be largely accounted for by genotype at these two risk variants. While not excluding effects on other genes in the region, this study implicates altered neural expression of BORCS7, AS3MT, and NT5C2 in susceptibility to schizophrenia arising from genetic variation at the chromosome 10q24 locus. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.