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

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.