Ignoring distant genealogic loops leads to false-positives in homozygosity mapping

Area of Science:

• Genetics
• Medical Genetics
• Bioinformatics

Background:

• Consanguineous loops are crucial in genetic analyses like homozygosity mapping.
• Distant consanguineous loops are frequently overlooked, potentially compromising study accuracy.

Purpose of the Study:

• To investigate the impact of unconsidered distant consanguineous loops on homozygosity mapping.
• To quantify the underestimation of consanguinity and the inflation of false-positive linkage results.

Main Methods:

• Theoretical evaluation of linkage analysis with and without distant loops.
• Analysis of 6 Alzheimer's disease patients to assess inbreeding contributions.
• Development of a hypothetical loop concept for comprehensive inbreeding capture.

Main Results:

• Distant loops can account for a significant portion of inbreeding (average 57.7% in AD patients).
• Ignoring distant loops inflates false-positive rates in 2-point linkage analysis by hundreds of times.
• A 5% empirical significance level in multipoint analysis showed a 11.1% true false positive rate when distant loops were ignored.

Conclusions:

• Failure to account for distant consanguineous loops significantly increases false-positive linkage results.
• Incorporating distant loops, or using a hypothetical loop, is essential for accurate genetic analyses.
• Genomic data can be used to construct hypothetical loops when extensive genealogical data is unavailable.