Combinatorial effects of gene dosage, polygenic background and environment on complex traits.
Complex traits arise from the combined effects of rare and common genetic variation, development and environment, but resolving their joint contributions has been limited by statistical power. Here, we meta-analyze effects of recurrent copy number variants (CNVs), polygenic scores, sex, age and medications on height and body mass index in 1,447,001 individuals across 6 biobanks and clinical cohorts. CNVs show largely mirror dose-dependent effects of deletions and duplications on both traits, but a subset of loci exhibit asymmetric dose-responses on adult height, consistent with buffering of one allele but not the other. Polygenic background and medications combine with CNVs in ways broadly consistent with additivity. However, detailed analyses of loci at 16p11.2 and 22q11.2 reveal context-dependent effects that vary across development, physiology and sex. At 22q11.2, the net effect of a CNV reflects opposing and reinforcing contributions of multiple genes, providing a potential mechanism for buffering of dosage effects. These results indicate that genetic effects follow additive patterns in aggregate, while context-dependent deviations are widespread for specific loci.
Authors
Sacks Sacks, Klein Klein, Bigdeli Bigdeli, Kals Kals, Oetjens Oetjens, Bénitière Bénitière, Johnson Johnson, Maihofer Maihofer, Nõukas Nõukas, Francis Francis, Gorman Gorman, Said Said, Genovese Genovese, Voloudakis Voloudakis, Markianos Markianos, Stein Stein, Gelernter Gelernter, Ledbetter Ledbetter, Nievergelt Nievergelt, Martin Martin, Bourque Bourque, Shanta Shanta, MacDonald MacDonald, Thiruvahindrapuram Thiruvahindrapuram, Ahangari Ahangari, Srinivasan Srinivasan, Guevara Guevara, Hall Hall, Haddon Haddon, Vingerhoets Vingerhoets, Linden Linden, van Haelst van Haelst, van den Bree van den Bree, Bearden Bearden, Gur Gur, Blaine Crowley Blaine Crowley, McGinn McGinn, Emanuel Emanuel, Zackai Zackai, Swillen Swillen, van Amelsvoort van Amelsvoort, Vorstman Vorstman, Bassett Bassett, McDonald-McGinn McDonald-McGinn, Roussos Roussos, Aslan Aslan, Harvey Harvey, , , , Jacquemont Jacquemont, Pyarajan Pyarajan, Lehto Lehto, Visscher Visscher, Sebat Sebat
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