Parent-of-Origin inference for biobanks

Area of Science:

• Genetics
• Genomics
• Human Biology

Background:

• Parent-of-origin effects, where genetic variations differ based on parental inheritance, are crucial for understanding phenotype variability.
• Previous studies on parent-of-origin effects were limited by small sample sizes due to the unavailability of parental genomes or detailed genealogies.

Purpose of the Study:

• To develop and validate a novel probabilistic method for inferring allele parent-of-origin without requiring parental genomes or known genealogies.
• To investigate parent-of-origin effects across a wide range of human phenotypes using a large dataset.

Main Methods:

• Utilized Identity-By-Descent (IBD) sharing with related individuals (second and third degree) to assign alleles to parental groups.
• Leveraged chromosome X data in males to differentiate maternal and paternal allele origins.
• Combined haplotype inference and haploid imputation to determine parent-of-origin for 26,393 individuals in the UK Biobank.

Main Results:

• Successfully inferred parent-of-origin for a large cohort, enabling screening of 99 phenotypes.
• Confirmed known parent-of-origin effects for body mass index, type 2 diabetes, standing height, and platelet phenotypes (e.g., MEG3/DLK1 locus).
• Discovered a novel maternal effect of the TERT gene on telomere length, offering new insights into its heritability.

Conclusions:

• The developed probabilistic method effectively infers allele parent-of-origin in large cohorts without parental data, overcoming previous limitations.
• The study identified significant parent-of-origin effects on various human health traits, including a new maternal effect on telomere length.
• Publicly available summary statistics will facilitate further research into the mechanisms and health implications of parent-of-origin effects.