The impact of genotype calling errors on family-based studies

Area of Science:

• Genetics
• Bioinformatics
• Statistical Genetics

Background:

• Family-based sequencing studies are valuable for identifying rare genetic variants.
• Standard genotype calling algorithms struggle with accurate rare variant detection, often misclassifying heterozygotes.

Purpose of the Study:

• To investigate the impact of genotyping errors on rare variant association tests in family-based sequence data.
• To assess how genotype calling errors affect the type I error rate and statistical power of transmission-based association tests.

Main Methods:

• Comprehensive simulation studies using realistic parameters for family-based sequencing.
• Analysis of exome sequence data from an autism research project to confirm simulation findings.

Main Results:

• Biased genotype calling errors were found to inflate the type I error rate (increase false positives).
• These errors also led to a significant loss of statistical power in association tests.
• Observations were validated using real-world exome sequence data from an autism cohort.

Conclusions:

• Non-symmetric genotype calling errors pose a significant challenge in family-based sequence data analysis.
• Careful consideration of these errors is crucial for reliable genetic association studies.
• Practical guidance is provided to mitigate bias in transmission-based tests for family studies.