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Combinatorial effects of gene dosage, polygenic background and environment on complex traits
Molly F Sacks1,2, Marieke Klein3, Tim B Bigdeli4,5,6,7
1Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
Summary
This study meta-analyzed copy number variants (CNVs) and polygenic scores in over 1.4 million people. It found that while genetic effects are generally additive, specific genetic loci show context-dependent variations impacting complex traits.
Area of Science:
- Genetics
- Human Physiology
- Bioinformatics
Background:
- Complex traits result from interactions between genetic variation, development, and environment.
- Resolving these joint contributions is challenging due to limitations in statistical power.
Purpose of the Study:
- To meta-analyze the effects of copy number variants (CNVs), polygenic scores, sex, age, and medications on height and body mass index.
- To investigate the joint contributions of genetic and non-genetic factors on complex traits in a large cohort.
Main Methods:
- Meta-analysis of data from 1,447,001 individuals across 6 biobanks and clinical cohorts.
- Analysis of recurrent CNVs, polygenic scores, sex, age, and medication effects on height and BMI.
- Detailed locus-specific analyses at 16p11.2 and 22q11.2.
Main Results:
- CNVs demonstrated largely dose-dependent effects on height and BMI, with some loci showing asymmetric responses.
- Polygenic background and medications combined with CNVs in an additive manner.
- Loci at 16p11.2 and 22q11.2 exhibited context-dependent effects varying with development, physiology, and sex.
Conclusions:
- Genetic effects on complex traits are predominantly additive in aggregate.
- Context-dependent deviations from additivity are widespread for specific genetic loci, particularly CNVs.
- Gene interactions within CNVs, such as at 22q11.2, can buffer dosage effects and explain complex trait variations.
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