Genome-wide copy number variation association study in anorexia nervosa

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Alicia Walker, Robert Karlsson, Jin P. Szatkiewicz, Laura M. Thornton, Zeynep Yilmaz, Virpi M. Leppä, Androula Savva, Tian Lin, Julia Sidorenko, Allan McRae, George Kirov, Helena L. Davies, Bengt T. Fundín, Samuel J. R. A. Chawner, Jie Song, Stina Borg, Jia Wen, Hunna J. Watson, Melissa A. Munn-Chernoff, Jessica H. Baker, Scott Gordon, Wade H. Berrettini, Harry Brandt, Steven Crawford, Katherine A. Halmi, Allan S. Kaplan, Walter H. Kaye, James Mitchell, Michael Strober, D. Blake Woodside, Nancy L. Pedersen, Richard Parker, Jennifer Jordan, Martin A. Kennedy, Andreas Birgegård, Mikael Landén, Nicholas G. Martin, Patrick F. Sullivan, Cynthia M. Bulik, Naomi R. Wray
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Abstract

This study represents the first large-scale investigation of rare (<1% population frequency) copy number variants (CNVs) in anorexia nervosa (AN). Large, rare CNVs are reported to be causally associated with anthropometric traits, neurodevelopmental disorders, and schizophrenia, yet their role in the genetic basis of AN is unclear. Using genome-wide association study (GWAS) array data from the Anorexia Nervosa Genetics Initiative (ANGI), which included 7414 AN case and 5044 controls, we investigated the association of 67 well-established syndromic CNVs and 178 pleiotropic disease-risk dosage-sensitive CNVs with AN. To identify novel CNV regions (CNVRs) that increase the risk of AN, we conducted genome-wide association studies with a focus on rare CNV-breakpoints (CNV-GWAS). We found no net enrichment of rare CNVs, either deletions or duplications, in AN, and none of the well-established syndromic or pleiotropic CNVs had a significant association with AN status. However, the CNV-GWAS found 21 nominally associated CNVRs that contribute to AN risk, covering protein-coding genes implicated in synaptic function, metabolic/mitochondrial factors, and lipid characteristics, like the CD36 (7q21.11) gene, which transports long-chain fatty acids into cells. CNVRs intersecting genes previously related to neurodevelopmental traits include deletions of NRXN1 intron 5 (2p16.3), IMMP2L (7q31.1), and PTPRD (9p23). Overall, given that our study is well powered to detect the CNV burden level reported for schizophrenia, we can conclude that rare CNVs have a limited role in the etiology of AN, as reported for bipolar disorder. Our nominal associations for the 21 discovered CNVRs are consistent with AN being a metabo-psychiatric trait, as demonstrated by the common genetic architecture of AN, and we provide association results to allow for replication in future research.

Abstract Image

神经性厌食症全基因组拷贝数变异关联研究
这项研究是对神经性厌食症(AN)中罕见(1%人群频率)拷贝数变异(CNVs)的首次大规模调查。据报道,大型罕见 CNV 与人体测量特征、神经发育障碍和精神分裂症有因果关系,但它们在神经性厌食症遗传基础中的作用尚不清楚。我们利用神经性厌食症基因倡议(ANGI)的全基因组关联研究(GWAS)阵列数据(包括7414例神经性厌食症病例和5044例对照),研究了67个成熟的综合征CNV和178个多向疾病风险剂量敏感CNV与神经性厌食症的关联。为了确定增加 AN 风险的新型 CNV 区域(CNVRs),我们进行了全基因组关联研究,重点关注罕见 CNV 断裂点(CNV-GWAS)。我们发现,罕见 CNV(缺失或重复)在 AN 中并没有净富集,而且没有一个已被证实的综合征或多向性 CNV 与 AN 状态有显著关联。然而,CNV-GWAS 发现了 21 个名义上与 AN 风险有关的 CNVR,涵盖了与突触功能、代谢/半胱氨酸因素和脂质特征(如将长链脂肪酸转运到细胞中的 CD36 (7q21.11) 基因)有关的蛋白编码基因。以前与神经发育特征相关的 CNVRs 交叉基因包括 NRXN1 内含子 5(2p16.3)、IMMP2L(7q31.1)和 PTPRD(9p23)的缺失。总之,鉴于我们的研究具有检测精神分裂症 CNV 负荷水平的良好效应,我们可以得出结论,罕见 CNV 在 AN 病因学中的作用有限,正如双相情感障碍的报道一样。我们发现的 21 个 CNVRs 的名义关联与 AN 是一种代谢精神病性状是一致的,AN 的共同遗传结构也证明了这一点,我们提供了关联结果,以便在未来的研究中进行复制。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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