Smart Sophie E, Legge Sophie E, Fenner Eilidh, Pardiñas Antonio F, Woolway Grace, Lynham Amy J, Escott-Price Valentina, Hall Jeremy, Wilkinson Lawrence, Holmans Peter, O'Donovan Michael C, Owen Michael J, Walters James T R
Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Neuroscience and Mental Health Innovation Institute, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Am J Med Genet B Neuropsychiatr Genet. 2025 Jun 18:e33037. doi: 10.1002/ajmg.b.33037.
The missense SNP NC_000004.12:g.102267552C>T (also known as SLC39A8.p.(Ala391Thr), rs13107325) in SLC39A8 encodes a zinc transporter. This SNP has been linked to schizophrenia and is the likely causal variant for one of the genome-wide association loci associated with the disorder. Using regression analyses, we tested whether the schizophrenia-risk allele at p.(Ala391Thr) was associated with schizophrenia-related phenotypes, including positive, negative, and disorganized symptoms, cognitive ability, educational attainment, and age of psychosis onset, within three schizophrenia cohorts (combined N = 1232) and, with equivalent phenotypes, in a sample of population controls (UK Biobank, N = 355,069). We also used the population controls to test for associations with rare protein-truncating and deleterious missense variants within SLC39A8. Within the schizophrenia cohorts, after correction for multiple testing, p.(Ala391Thr) was not significantly associated with any schizophrenia-related phenotypes. In the unaffected participants from the UK Biobank, the schizophrenia-risk allele at p.(Ala391Thr) was associated with significantly poorer cognitive ability and fluid intelligence, a lower probability of obtaining GCSEs or a degree-level qualification, and fewer years in education. There was no association between p.(Ala391Thr) and self-reported psychotic experiences in this cohort. Rare variants in SLC39A8 were nominally associated with poorer cognitive ability, but these associations did not survive correction for multiple testing. The schizophrenia-risk allele was associated with poorer cognitive ability, but not psychotic experiences, in a volunteer sample drawn from the general population. We found no evidence that p.(Ala391Thr) was associated with symptom severity in schizophrenia. To understand the impact of rare variants in SLC39A8 on cognitive impairment, larger independent samples are required.
溶质载体家族39成员8（SLC39A8）基因中的错义单核苷酸多态性（SNP）NC_000004.12:g.102267552C>T（也称为SLC39A8.p.(Ala391Thr)，rs13107325）编码一种锌转运蛋白。该SNP与精神分裂症有关，并且可能是与该疾病相关的全基因组关联位点之一的因果变异。我们使用回归分析，在三个精神分裂症队列（合并样本量N = 1232）中，以及在一个具有同等表型的人群对照样本（英国生物银行，N = 355,069）中，测试了p.(Ala391Thr)位点的精神分裂症风险等位基因是否与精神分裂症相关表型有关，这些表型包括阳性、阴性和紊乱症状、认知能力、教育程度以及精神病发作年龄。我们还利用人群对照样本测试SLC39A8基因内罕见的蛋白质截短和有害错义变异的关联性。在精神分裂症队列中，经过多重检验校正后，p.(Ala391Thr)与任何精神分裂症相关表型均无显著关联。在英国生物银行的未患病参与者中，p.(Ala391Thr)位点的精神分裂症风险等位基因与显著较差的认知能力和流体智力、获得普通中等教育证书（GCSEs）或学位水平资格的概率较低以及受教育年限较少有关。在该队列中，p.(Ala391Thr)与自我报告的精神病体验之间没有关联。SLC39A8基因中的罕见变异名义上与较差的认知能力有关，但这些关联在多重检验校正后未成立。在从普通人群中抽取的一个志愿者样本中，精神分裂症风险等位基因与较差的认知能力有关，但与精神病体验无关。我们没有发现证据表明p.(Ala391Thr)与精神分裂症的症状严重程度有关。为了了解SLC39A8基因中罕见变异对认知障碍的影响，需要更大的独立样本。
