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 carriers among unrelated white British UK Biobank participants, we performed a phenome-wide association study 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 thirty, ten, four, and two phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, cognitive function, or socio-economic status as potential mediators, we found that sixteen testable deletion-driven associations (61%) − primarily with cardiovascular and metabolic traits − were BMI-dependent, with other mediators playing a more subtle role. Bidirectional Mendelian randomization supported that 13 out of these 16 associations (81%) were secondary consequences of the CNV′s impact on BMI. For the 22 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that eleven phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, pulmonary capacity, pneumonia, and acute kidney injury, remained associated under strict Bonferroni correction, with eight 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 cognition, acting through trait-specific dosage mechanisms.

中文翻译：

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解开近端 16p11.2 BP4-5 CNV 多效性效应背后的机制

尽管 16p11.2 BP4-5 拷贝数变异 (CNV) 代表了临床和人群队列中基因组综合征最具多效性的病因之一，但导致这种多效性的机制仍未得到充分研究。我们在不相关的英国英国生物银行白人参与者中鉴定出 73 个缺失和 89 个重复携带者，并模拟了四种剂量模型，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。 46 个表型 (39%) 受到 16p11.2 BP4-5 CNV 的影响，仅删除、镜像、U 形和仅重复模型最适合 30、10、4 和 2 个表型，分别与删除的更强有害性相一致。在单独调整体重指数 (BMI)、身高、认知功能或社会经济地位作为潜在中介因素的 CNV 效应后，我们发现 16 个可测试的删除驱动关联 (61%)（主要与心血管和代谢特征相关）被BMI 依赖性，其他调节因素发挥着更微妙的作用。双向孟德尔随机化支持这 16 个关联中的 13 个 (81%) 是 CNV 对 BMI 影响的次要后果。对于在个体调整中介因素后仍然显着相关的 22 个特征，匹配对照分析发现，在严格的条件下，包括肌肉骨骼特征、肝酶、液体智力、血小板计数、肺活量、肺炎和急性肾损伤在内的 11 种表型仍然相关。 Bonferroni 校正，还有八个名义上显着的关联。这些结果描绘了 16p11.2 BP4-5 的多效性模式的复杂图景，该模式涉及对多个生理系统的直接影响以及 CNV 对 BMI 和认知的影响所导致的间接共病，通过性状特异性剂量机制发挥作用。