Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Center for Primary Care and Public Health, Lausanne, Switzerland.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Center for Primary Care and Public Health, Lausanne, Switzerland.
Am J Hum Genet. 2024 Nov 7;111(11):2347-2361. doi: 10.1016/j.ajhg.2024.08.014. Epub 2024 Sep 26.
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.
虽然 16p11.2BP4-5 拷贝数变异 (CNV) 是临床和人群队列中基因组综合征的最具多效性病因之一，但导致这种多效性的机制仍未得到充分研究。在英国生物银行的非相关白种英国参与者中，我们鉴定了 73 个缺失和 89 个重复携带者个体，在该区域的拷贝数与 117 种复杂特征和疾病之间进行了全表型关联研究 (PheWAS)，模拟了四种剂量模型。46 种表型（39%）受 16p11.2BP4-5CNV 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 种表型，与缺失的更强有害性一致。当单独调整 CNV 对体重指数 (BMI)、身高或教育程度 (EA) 的影响时，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相关——是 BMI 依赖性的，EA 发挥更微妙的作用，而与身高无关。双向 Mendelian 随机化支持这 16 个关联中的 13 个是 CNV 对 BMI 影响的次级后果。对于在单独调整中介物后仍然显著相关的 23 个特征，匹配对照分析发现，10 种表型，包括肌肉骨骼特征、肝酶、流体智力、血小板计数以及肺炎和急性肾损伤风险，在严格的 Bonferroni 校正下仍然相关，另外还有 10 个具有名义意义的关联。这些结果描绘了 16p11.2BP4-5 多效性模式的复杂图景，涉及对多个生理系统的直接影响，以及由于 CNV 对 BMI 和 EA 的影响而导致的间接合并症，通过特定特征的剂量机制起作用。
