欧洲人群的全基因组关联研究(GWAS)已经确定了100多个精神分裂症相关基因座。在一个独特的印度人群中,精神分裂症GWAS提供了新的发现。
在一个独特的印度人群的GWAS中发现和功能评估精神分裂症的遗传位点。
这个GWAS包括受影响个体的样本,家庭成员,以及无关的病例和对照。招募了三千九十二人,并通过医疗记录进行了诊断。医院,诊所,以及钦奈和周边地区的临床网络。受影响的参与者符合DSM-IV精神分裂症的诊断标准。不相关的对照参与者没有精神病的个人或家族史。招聘,基因分型,和分析从2001年1月1日开始连续进行。招聘已于2018年2月28日完成,基因分型和分析正在进行中。
单核苷酸多态性和基因表达与精神分裂症的关联.
研究人群包括1321名精神分裂症患者,885个家庭控制,和886个无关的控件。在精神分裂症患者中,平均(SD)年龄为39.1(11.4)岁,52.7%为男性。这个样本显示出统一的种族,一定程度的近亲繁殖,和可忽略不计的药物滥用率。在精神分裂症和染色体8q24.3基因座之间观察到了一种新的全基因组显着关联(rs10866912,等位基因A;比值比[OR],1.27[95%CI,1.17-1.38];P=4.35×10-8)吸引了精神分裂症精神病学基因组学联盟2数据(rs10866912,等位基因A;OR,1.04[95%CI,1.02-1.06];P=7.56×10-4)。这个地点经历了自然选择,风险等位基因A的频率从印度(约72%)下降到欧洲(约43%)。rs10866912直接修饰大脑皮层中烟酸磷酸核糖基转移酶基因(NAPRT1)转录物的丰度(归一化效应大小,0.79;95%CI,0.6-1.0;P=5.8×10-13)。NAPRT1编码烟酸代谢的关键酶。在印度淋巴母细胞细胞系中,rs10866912的(风险)等位基因A与NAPRT1下调相关(AA:0.74,n=21;CC:1.56,n=17;P=.004)。斑马鱼的初步数据进一步表明,NAPRT1功能的部分丧失会导致大脑发育异常。
生物信息学分析以及细胞和斑马鱼基因表达研究暗示NAPRT1是一种新的易感基因。鉴于该基因在烟酸代谢中的作用,以及烟酸缺乏引起神经精神疾病如糙皮病和Hartnup病中精神分裂症症状的证据,这些结果表明rs10866912基因型和烟酸状态可能对精神分裂症易感性和治疗有影响。
Genome-wide association studies (GWASs) in European populations have identified more than 100 schizophrenia-associated loci. A schizophrenia GWAS in a unique Indian population offers novel findings.
To discover and functionally evaluate genetic loci for schizophrenia in a GWAS of a unique Indian population.
This GWAS included a sample of affected individuals, family members, and unrelated cases and controls. Three thousand ninety-two individuals were recruited and diagnostically ascertained via medical records, hospitals, clinics, and clinical networks in Chennai and surrounding regions. Affected participants fulfilled DSM-IV diagnostic criteria for schizophrenia. Unrelated control participants had no personal or family history of psychotic disorder. Recruitment, genotyping, and analysis occurred in consecutive phases beginning January 1, 2001. Recruitment was completed on February 28, 2018, and genotyping and analysis are ongoing.
Associations of single-nucleotide polymorphisms and gene expression with schizophrenia.
The
study population included 1321 participants with schizophrenia, 885 family controls, and 886 unrelated controls. Among participants with schizophrenia, mean (SD) age was 39.1 (11.4) years, and 52.7% were male. This sample demonstrated uniform ethnicity, a degree of inbreeding, and negligible rates of substance abuse. A novel genome-wide significant association was observed between schizophrenia and a chromosome 8q24.3 locus (rs10866912, allele A; odds ratio [OR], 1.27 [95% CI, 1.17-1.38]; P = 4.35 × 10-8) that attracted support in the schizophrenia Psychiatric Genomics Consortium 2 data (rs10866912, allele A; OR, 1.04 [95% CI, 1.02-1.06]; P = 7.56 × 10-4). This locus has undergone natural selection, with the risk allele A declining in frequency from India (approximately 72%) to Europe (approximately 43%). rs10866912 directly modifies the abundance of the nicotinate phosphoribosyltransferase gene (NAPRT1) transcript in brain cortex (normalized effect size, 0.79; 95% CI, 0.6-1.0; P = 5.8 × 10-13). NAPRT1 encodes a key enzyme for niacin metabolism. In Indian lymphoblastoid cell lines, (risk) allele A of rs10866912 was associated with NAPRT1 downregulation (AA: 0.74, n = 21; CC: 1.56, n = 17; P = .004). Preliminary zebrafish data further suggest that partial loss of function of NAPRT1 leads to abnormal brain development.
Bioinformatic analyses and cellular and zebrafish gene expression studies implicate NAPRT1 as a novel susceptibility gene. Given this gene\'s role in niacin metabolism and the evidence for niacin deficiency provoking schizophrenialike symptoms in neuropsychiatric diseases such as pellagra and Hartnup disease, these results suggest that the rs10866912 genotype and niacin status may have implications for schizophrenia susceptibility and treatment.