A multi-locus likelihood method for assessing parent-of-origin effects using case-control mother-child pairs

Area of Science:

• Genetics and Genomics
• Reproductive Health
• Statistical Genetics

Background:

• Parent-of-origin effects are a potential source of heritability not explained by genome-wide association studies.
• Standard case-control designs lack the parental information needed to effectively study these effects.
• Mother-child pair designs offer a powerful alternative for assessing parent-of-origin effects.

Purpose of the Study:

• To develop and evaluate a case-control mother-child pair design for studying parent-of-origin effects on neonatal/early-life disorders and pregnancy-related conditions.
• To investigate the power increase for detecting parent-of-origin effects by incorporating genotype data from adjacent markers in linkage disequilibrium (LD).

Main Methods:

• Utilized a maximum likelihood method to simultaneously assess parental sources and estimate offspring genotype effect sizes.
• Incorporated genotype data from adjacent markers in LD with the test locus to enhance parent-of-origin information recovery.
• Applied the method to simulated SNP data and real data from the Jerusalem Perinatal Study.

Main Results:

• Analysis of simulated data indicated that incorporating adjacent marker genotypes significantly aids in recovering parent-of-origin information.
• This recovery can lead to a substantial improvement in statistical power for detecting parent-of-origin effects.
• Demonstrated the method's utility by examining parent-of-origin effects of PPARGC1A on low birth weight.

Conclusions:

• The mother-child pair design, especially when enhanced with adjacent marker data, provides a powerful approach for studying parent-of-origin effects.
• This methodology can improve the detection of genetic influences on early-life conditions and pregnancy outcomes.
• The findings contribute to understanding the heritability gap and identifying novel genetic associations.