Parent-of-origin effects on complex traits in up to 236,781 individuals

Area of Science:

• Genetics
• Evolutionary Biology
• Human Complex Traits

Background:

• Parent-of-origin effects (POEs) are genetic influences dependent on parental inheritance, traditionally linked to genomic imprinting and parental conflict.
• POEs are crucial for understanding complex traits but remain underexplored due to challenges in inferring allele origin without parental genomes.

Purpose of the Study:

• To develop and apply a novel computational approach for inferring the parent of origin of alleles without requiring parental genomes.
• To investigate the contribution of POEs to diverse complex human traits and protein quantitative trait loci (pQTLs).

Main Methods:

• Leveraged interchromosomal phasing, mitochondrial and X chromosome data, and sex-specific crossover in siblings for parent-of-origin inference.
• Applied the method to large biobanks (UK Biobank, Estonian Biobank) and a family cohort (MoBa) for genome-wide association studies (GWAS) and pQTL analyses.
• Contrasted maternal and paternal effects to identify and validate POEs across 59 complex traits.

Main Results:

• Successfully inferred parent-of-origin for a large cohort (up to 109,385 individuals) and identified over 30 novel POEs for complex traits and pQTLs.
• Confirmed over 50% of known associations and found that over one-third of identified POEs exhibit opposing maternal and paternal influences, particularly in growth and metabolism traits.
• Validated 87% of testable associations in independent cohorts, underscoring the robustness of the findings.

Conclusions:

• The study presents a powerful new method for POE inference, significantly advancing the study of complex traits.
• Findings highlight the substantial, yet often overlooked, contribution of POEs to human phenotypic variation, supporting the parental conflict hypothesis.
• Provides compelling evidence for POEs as an important evolutionary phenomenon influencing human health and development.