Exonic Variation and Its Clinical Impact in 7221 Old Order Amish

Area of Science:

• Genomics
• Population Genetics
• Human Health

Background:

• The Amish population in Lancaster County, PA, exhibits unique demographic history, including a bottleneck and genetic drift.
• This history has led to reduced genetic diversity and increased frequency of specific genetic variants impacting health.

Purpose of the Study:

• To characterize coding variation in the Amish genome.
• To compare genetic diversity between Amish and European populations (UK Biobank).
• To assess the clinical implications of genetic variants in the Amish community.

Main Methods:

• Whole exome sequencing of 7221 adult Amish individuals.
• Comparison of variant data with UK Biobank European participants.
• Identification and classification of pathogenic (P) and likely pathogenic (LP) variants using ClinVar and a population-specific panel.

Main Results:

• Amish exomes contained 14% of the variants found in an equal number of UK Biobank participants, indicating reduced diversity.
• A high enrichment of P/LP variants was observed in the Amish population.
• 5.2% of Amish individuals were homozygous for recessive P/LP variants, and 25.6% were heterozygous for dominant P/LP variants.
• Significant carrier rates for autosomal recessive diseases were found in Amish couples (24.3%).

Conclusions:

• Reduced genetic diversity in the Amish is linked to a high burden of pathogenic variants with significant clinical implications.
• Founder effects and genetic drift have shaped the genetic landscape and health of the Amish community.
• Findings highlight the importance of genetic screening in founder populations and have broader implications for understanding human health and disease.