Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal.

IF 1.6 3区 医学 Q3 GENETICS & HEREDITY American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Pub Date : 2024-10-30 DOI:10.1002/ajmg.b.33011
I Claus, S Sivalingam, A C Koller, A Weiß, C M Mathey, L Sindermann, D Klein, L Henschel, K U Ludwig, P Hoffmann, A Heimbach, S Heilmann-Heimbach, H Vedder, J Kammerer-Ciernioch, T Stürmer, F Streit, A Maaser-Hecker, I Nenadić, B T Baune, A M Hartmann, B Konte, I Giegling, U Heilbronner, M Wagner, A Philipsen, B Schmidt, D Rujescu, A Buness, T G Schulze, M Rietschel, A J Forstner, M M Nöthen, F Degenhardt
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Abstract

Duplications of the Xq28,distal locus have been described in male and female patients with schizophrenia (SCZ) or intellectual disability. The Xq28,distal locus spans eight protein-coding genes (F8, CMC4, MTCP1, BRCC3, VBP1, FUNDC2, CLIC2, and RAB39B) and is flanked by recurrent genomic breakpoints. Thus, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. The aim of this study was to investigate the contribution of rare and potentially functionally relevant sequence variants within the Xq28,distal locus to SCZ risk using the single-molecule molecular inversion probes (smMIP) method. Targeted sequencing was performed in a cohort of 1935 patients with SCZ and 1905 controls of European ancestry. The consecutive statistical analysis addressed two main areas. On the level of the individual variants, allele counts in the patient and control cohort were systematically compared with a Fisher's exact test: (i) for the entire present study cohort; (ii) for patients and controls separated by sex; and (iii) in combination with data published by the Schizophrenia Exome Meta-Analysis (SCHEMA) consortium. On the gene-wise level, a burden analysis was performed using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test (SKAT-O), with adjustment for possible sex-specific effects. Targeted sequencing identified a total of 13 rare and potentially functional variants in four patients and 11 controls. However, neither at the level of individual rare and potentially functional variants nor at the level of the eight protein-coding genes at the Xq28,distal locus was a statistically significant enrichment in patients compared to controls observed. Although inconclusive, the present findings represent a step toward improved understanding of the contribution of X-chromosomal risk factors in neuropsychiatric disorder development, which is an underrepresented aspect of genetic studies in this field.

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精神分裂症风险病灶 Xq28 远端罕见和潜在功能相关序列变异的贡献
在患有精神分裂症(SCZ)或智力障碍的男性和女性患者中,都曾出现过 Xq28 远端位点的重复。Xq28远端位点横跨八个蛋白质编码基因(F8、CMC4、MTCP1、BRCC3、VBP1、FUNDC2、CLIC2和RAB39B),两侧是反复出现的基因组断点。因此,该基因位点上的哪些基因与 SCZ 发病机制相关的问题仍不清楚。本研究的目的是利用单分子分子反转探针(smMIP)方法,研究Xq28远端位点上罕见且可能与功能相关的序列变异对SCZ风险的贡献。对1935名SCZ患者和1905名欧洲血统的对照组进行了靶向测序。连续统计分析主要涉及两个方面。在单个变异的层面上,通过费雪精确检验系统地比较了患者和对照组的等位基因数:(i) 本研究的整个队列;(ii) 按性别区分的患者和对照组;(iii) 结合精神分裂症外显子组元分析(SCHEMA)联盟公布的数据。在基因层面,使用最优统一序列核关联检验(SKAT-O)的 X 染色体模型进行了负荷分析,并对可能的性别特异性效应进行了调整。在 4 名患者和 11 名对照组中,靶向测序共发现了 13 个罕见的潜在功能变异。然而,与对照组相比,无论是在单个罕见和潜在功能变异的水平上,还是在Xq28远端位点的八个蛋白编码基因的水平上,都没有观察到患者的罕见和潜在功能变异在统计学上有显著的富集。尽管尚无定论,但本研究结果标志着我们朝着更好地了解 X 染色体风险因素在神经精神疾病发展中的作用迈出了一步,而这正是该领域遗传研究中代表性不足的一个方面。
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来源期刊
CiteScore
5.90
自引率
7.10%
发文量
40
审稿时长
4-8 weeks
期刊介绍: Neuropsychiatric Genetics, Part B of the American Journal of Medical Genetics (AJMG) , provides a forum for experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. It is a resource for novel genetics studies of the heritable nature of psychiatric and other nervous system disorders, characterized at the molecular, cellular or behavior levels. Neuropsychiatric Genetics publishes eight times per year.
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Issue Information - TOC Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal. Optimizing the Prediction of Depression Remission: A Longitudinal Machine Learning Approach. New Insights Into TRMT10A Syndrome: Case Report and Literature Review. Characterization of Two Novel PNKP Splice-Site Variants in a Proband With Microcephaly, Intellectual Disability, and Multiple Malformations.
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