Genetically isolated populations that have arisen due to recent bottleneck events have reduced genetic variation that reflect the common set of founders. Many genetic variants that are rare in the general population drift to a high frequency in isolate populations, including some variants causing rare Mendelian diseases. The Old Order Amish of Lancaster County, PA, are a population isolate that are largely descendants of <200 of the original settlers. The unique genetic, cultural, and environmental homogeneity of the Amish is reinforced by the cultural proclivity to marry within the community. The overall theme of this thesis is to evaluate the impact of limited genetic diversity on reproductive outcomes and other traits of biomedical importance. This theme is addressed through three complementary sub-studies, each considering a different aspect of the impact of genetic homogeneity on the health of the Amish. In the first sub-study, seven pathogenic/likely pathogenic (P/LP) variants were identified within genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger’s My Code Health Initiative. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. The Amish harbor fewer actionable variants compared to similarly characterized non-founder populations but have a higher frequency of each variant identified. The second sub-study assessed the burden of parental relatedness on reproductive health. Amish couples who were both heterozygous carriers of a highly penetrant P/LP variant experienced fewer number of miscarriages than non-carrier couples from the same Amish community. In addition, overall genetic relatedness between spouses was highly correlated with number of live births (p <0.0001), pregnancies (p <0.0001), and stillbirths (p=0.03). The third sub-study evaluated autozygosity (FROH), the portion of the genome that is homozygous by descent. Measurements of genome-wide and regional FROH were used as the primary predictors of trait variation in association analysis of 96 traits. No associations were identified when assessing genome-wide autozygosity measurements, but regional FROH estimation revealed two regions in which increased autozygosity was associated with increased trait values.