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.

中文翻译：

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解开近端 16p11.2 BP4-5 CNV 多效性作用背后的机制


虽然 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。在无关的 White British UK Biobank 参与者中确定了 73 个缺失和 89 个重复携带者个体，我们在该区域的拷贝数与 117 个复杂特征和疾病之间进行了全表型组关联研究 （PheWAS），模拟了四种剂量模型。46 个表型 （39%） 受 16p11.2 BP4-5 CNV 影响，其中仅缺失、镜像、U 形和仅重复模型分别最适合 30 、 10 、 4 和 2 个表型，与缺失的更强有害性一致。在单独调整体重指数 （BMI） 、身高或教育程度 （EA） 的 CNV 效应后，我们发现 16 个可测试的缺失驱动关联（主要与心血管和代谢特征有关）是 BMI 依赖性的，其中 EA 起着更微妙的作用，没有关联取决于身高。双向孟德尔随机化支持这 16 个关联中有 13 个是 CNV 对 BMI 影响的次要后果。对于在个体调整介质时仍显著相关的 23 个性状，匹配对照分析发现，在严格的 Bonferroni 校正下，10 种表型，包括肌肉骨骼性状、肝酶、体液智力、血小板计数以及肺炎和急性肾损伤风险，以及另外 10 个名义上显着的关联。这些结果描绘了 16p11 的复杂图景。2 BP4-5 的多效性模式涉及对多个生理系统的直接影响和间接合并症，这些并发症与 CNV 对 BMI 和 EA 的影响有关，通过性状特异性剂量机制起作用。