ABSTRACT
BACKGROUND: As precision medicine advances, polygenic scores (PGS) have become increasingly important for clinical risk assessment. Many methods have been developed to create polygenic models with increased accuracy for risk prediction. Our select and shrink with summary statistics (S4) PGS method has previously been shown to accurately predict the polygenic risk of epithelial ovarian cancer. Here, we applied S4 PGS to 12 phenotypes for UK Biobank participants, and compared it with the LDpred2 and a combined S4 + LDpred2 method. RESULTS: The S4 + LDpred2 method provided overall improved PGS accuracy across a variety of phenotypes for UK Biobank participants. Additionally, the S4 + LDpred2 method had the best estimated PGS accuracy in Finnish and Japanese populations. We also addressed the challenge of limited genotype level data by developing the PGS models using only GWAS summary statistics. CONCLUSIONS: Taken together, the S4 + LDpred2 method represents an improvement in overall PGS accuracy across multiple phenotypes and populations.
Subject(s)
Genome-Wide Association Study , Multifactorial Inheritance , Humans , Genome-Wide Association Study/methods , Phenotype , Polymorphism, Single Nucleotide , Models, Genetic , FemaleABSTRACT
The genetic consequences of species-wide declines are rarely quantified because the timing and extent of the decline varies across the species' range. The sea otter (Enhydra lutris) is a unique model in this regard. Their dramatic decline from thousands to fewer than 100 individuals per population occurred range-wide and nearly simultaneously due to the 18th-19th century fur trade. Consequently, each sea otter population represents an independent natural experiment of recovery after extreme population decline. We designed sequence capture probes for 50 Mb of sea otter exonic and neutral genomic regions. We sequenced 107 sea otters from five populations that span the species range to high coverage (18-76×) and three historical Californian samples from ~1500 and ~200 years ago to low coverage (1.5-3.5×). We observe distinct population structure and find that sea otters in California are the last survivors of a divergent lineage isolated for thousands of years and therefore warrant special conservation concern. We detect signals of extreme population decline in every surviving sea otter population and use this demographic history to design forward-in-time simulations of coding sequence. Our simulations indicate that this decline could lower the fitness of recovering populations for generations. However, the simulations also demonstrate how historically low effective population sizes prior to the fur trade may have mitigated the effects of population decline on genetic health. Our comprehensive approach shows how demographic inference from genomic data, coupled with simulations, allows assessment of extinction risk and different models of recovery.
Subject(s)
Otters , Humans , Animals , Otters/genetics , Population Density , GenomicsABSTRACT
BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13â071 EOC cases and 17â306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.