Genetic overlap between idiopathic scoliosis and schizophrenia in the general population.

IF 1.6 Q3 CLINICAL NEUROLOGY Spine deformity Pub Date : 2024-10-15 DOI:10.1007/s43390-024-00979-9
Steven de Reuver, Worrawat Engchuan, Nickie Safarian, Mehdi Zarrei, Jacob A S Vorstman, René M Castelein, Elemi J Breetvelt
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Abstract

Introduction: Adolescent idiopathic scoliosis (AIS) and schizophrenia (SCZ) are two distinct conditions with poorly understood aetiologies that both emerge in otherwise healthy young adolescents. One rare genetic condition associated with both phenotypic outcomes is the 22q11.2 deletion (22q11DS). This microdeletion, encompassing 47 genes, occurs in approximately 1 in 2,148 live births and confers a 20-fold higher risk for both AIS and schizophrenia compared to the general population. In the general population (non-22q11DS carriers), AIS and SCZ have also been reported to be related and genetic studies suggest the involvement of genetic variants implicated in the central nervous functioning. In this study, our objective was to further investigate genetic overlaps between these conditions in the general population. Specifically, we aimed to explore the role of genes within the 22q11.2 region, not only in terms of common variants but also their potential impact on gene networks and biopathways.

Methods: We used summary statistics from three genome-wide association studies (GWAS): two focused on AIS (n = 11,210), and one on schizophrenia (n = 36,989). To explore potential overlaps between the two conditions, we conducted a comparative analysis on the significance-based ranked single nucleotide polymorphisms (SNPs) that are associated with both AIS and SCZ. Next, we employed in silico analyses to assess gene-networks enrichment for the most significant SNPs and investigate the contribution of genes within the 22q11.2 region. Post-hoc analysis was conducted to explore the biological pathways correlated with SNPs significantly associated with both AIS and SCZ.

Results: The in silico analyses revealed a significant (adjusted-p < 0.05) genetic overlap between SCZ and both AIS cohorts. The top 3% of the most significant SNPs associated with both conditions exhibited a distinct enrichment cluster which is unlikely to be a result of chance (p < 3e-04). The gene-networks analyses showed a significant overlap of 26-41% with the ones involving genes in the 22q11DS region. However, there was no overlap between SNPs in this region and the most significant SNPs identified in the GWAS.

Conclusion: This study revealed compelling evidence that beyond the shared association with 22q11DS as a rare genetic variant, AIS and SCZ exhibit common genetic risk variants and an overlap of important genes. The gene networks enriched by the most significant SNPs for both conditions also intersect with the ones involving genes in the 22q11DS region. However, SNPs within this region were not overrepresented among the most significant SNPs from GWAS for both conditions. Notably, gene networks linked to the risk for both conditions suggest an involvement of biopathways related to cellular signaling and neuronal development.

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特发性脊柱侧凸与精神分裂症在普通人群中的遗传重叠。
导言:青少年特发性脊柱侧弯症(AIS)和精神分裂症(SCZ)是两种不同的疾病,其病因尚不清楚,但都出现在原本健康的青少年身上。22q11.2缺失(22q11DS)是与这两种表型结果相关的一种罕见遗传病。这种微缺失包括 47 个基因,大约每 2,148 个活产婴儿中就有 1 个会出现这种情况,与普通人群相比,AIS 和精神分裂症的患病风险高出 20 倍。据报道,在普通人群(非 22q11DS 携带者)中,AIS 和 SCZ 也是相关的,遗传研究表明,与中枢神经功能有关的基因变异也参与其中。在本研究中,我们的目标是进一步调查普通人群中这两种疾病之间的遗传重叠。具体而言,我们旨在探索 22q11.2 区域内基因的作用,这不仅体现在常见变异上,还体现在它们对基因网络和生物通路的潜在影响上:我们使用了三项全基因组关联研究(GWAS)的汇总统计数据:两项研究以 AIS(n = 11,210 个)为重点,一项研究以精神分裂症(n = 36,989 个)为重点。为了探索这两种疾病之间可能存在的重叠,我们对与 AIS 和 SCZ 相关的单核苷酸多态性(SNPs)进行了基于显著性排序的比较分析。接下来,我们采用硅分析评估了最重要 SNP 的基因网络富集情况,并调查了 22q11.2 区域内基因的贡献。我们还进行了事后分析,以探索与AIS和SCZ显著相关的SNP相关的生物通路:硅学分析表明,22q11.2 区域的 SNPs 与 AIS 和 SCZ 有显著的相关性(调整后-p):这项研究揭示了令人信服的证据,即除了与 22q11DS 这一罕见遗传变异有共同关联外,AIS 和 SCZ 还表现出共同的遗传风险变异和重要基因的重叠。这两种疾病最重要的 SNPs 所富集的基因网络也与涉及 22q11DS 区域基因的网络相交。然而,在这两种疾病的全球基因组研究中,该区域内的 SNPs 在最重要的 SNPs 中并没有过高的代表性。值得注意的是,与这两种疾病风险相关的基因网络表明,与细胞信号传导和神经元发育相关的生物通路也参与其中。
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来源期刊
CiteScore
3.20
自引率
18.80%
发文量
167
期刊介绍: Spine Deformity the official journal of the?Scoliosis Research Society is a peer-refereed publication to disseminate knowledge on basic science and clinical research into the?etiology?biomechanics?treatment?methods and outcomes of all types of?spinal deformities. The international members of the Editorial Board provide a worldwide perspective for the journal's area of interest.The?journal?will enhance the mission of the Society which is to foster the optimal care of all patients with?spine?deformities worldwide. Articles published in?Spine Deformity?are Medline indexed in PubMed.? The journal publishes original articles in the form of clinical and basic research. Spine Deformity will only publish studies that have institutional review board (IRB) or similar ethics committee approval for human and animal studies and have strictly observed these guidelines. The minimum follow-up period for follow-up clinical studies is 24 months.
期刊最新文献
18th International Congress on Early Onset Scoliosis and the Growing Spine : November 13-15, 2024 Scottsdale, Arizona, USA. A team approach to improve outcomes in pediatric scoliosis surgery: a review of the current literature. Research trends of biomechanics in scoliosis from 1999 to 2023: a bibliometric analysis. Is the information provided by large language models valid in educating patients about adolescent idiopathic scoliosis? An evaluation of content, clarity, and empathy : The perspective of the European Spine Study Group. What imaging does my AIS patient need? A multi-group survey of provider preferences.
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