Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-09-26 DOI:10.1016/j.ajhg.2024.08.014
Chiara Auwerx, Samuel Moix, Zoltán Kutalik, Alexandre Reymond
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Abstract

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region's copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV's impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5's pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV's impact on BMI and EA, acting through trait-specific dosage mechanisms.

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厘清近端 16p11.2 BP4-5 CNV 多效应背后的机制。
在临床和人群队列中,16p11.2 BP4-5 拷贝数变异(CNVs)是基因组综合征最具多义性的病因之一,但导致这种多义性的机制仍未得到充分研究。我们在无血缘关系的英国白人生物库参与者中发现了 73 个缺失和 89 个重复携带者,并模拟四种剂量模型对该区域的拷贝数与 117 种复杂性状和疾病之间进行了全表型关联研究(PheWAS)。有 46 种表型(39%)受到 16p11.2 BP4-5 CNV 的影响,其中纯缺失模型、镜像模型、U 型模型和纯重复模型分别对 30、10、4 和 2 种表型的拟合效果最好,这与缺失的强缺失性一致。在根据体重指数(BMI)、身高或教育程度(EA)对 CNV 影响进行单独调整后,我们发现 16 种可检验的缺失驱动关联--主要与心血管和代谢特征相关--都依赖于体重指数,而教育程度则起着更微妙的作用,与身高没有关联。双向孟德尔随机化证明,在这 16 种关联中,有 13 种是 CNV 对 BMI 影响的次要结果。在对中介因素进行个体调整后,23 个性状仍存在显著相关性,匹配对照分析发现,在严格的 Bonferroni 校正下,10 个表型(包括肌肉骨骼性状、肝酶、体液智力、血小板计数、肺炎和急性肾损伤风险)仍存在相关性,另有 10 个表型存在名义上的显著相关性。这些结果描绘了 16p11.2 BP4-5 多生物效应模式的复杂图景,其中包括对多个生理系统的直接影响,以及 CNV 通过性状特异性剂量机制对 BMI 和 EA 的影响所导致的间接并发症。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
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