Biomedical subjects

Daniel E Weeks

Publications and source records attributed to Daniel E Weeks.

3 recordsLinked to original sources

PubMed2026

The Soifua Manuia reference panel with 2,570 Samoan haplotypes improves genotype imputation quality among Samoans.

Genotype imputation is fundamental to association studies, and yet even gold standard panels like TOPMed are limited in the populations for which they yield good imputation. Specifically, Pacific Islanders are poorly represented in extant panels. To address this, we used whole-genome sequencing from 1,285 Samoan individuals combined with 1000 Genomes Project (1KGP) individuals to construct an imputation reference panel that better represents Pacific Islander, specifically Samoan, genetic variation. Here we show that this panel yielded up to two times more well-imputed (r2 ≥ 0.80) variants than TOPMed-R3 and 1KGP and was enriched for moderate and high impact variants. There was improved imputation accuracy across the minor allele frequency (MAF) spectrum; accuracy (r2) was greater for population-specific variants (high fixation index, FST) and those from larger haplotypes (high LD score). However, the gain in accuracy over TOPMed-R3 was largest for small haplotypes, reflecting the Samoan panel's ability to capture variation not well tagged by other panels.

Haplotypes↗

PubMed2026

Variant harmonization critically determines polygenic score transferability for lipid traits in Samoan populations.

Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa. Polygenic scores (PGSs) for lipid traits offer promise for improved CVD risk prediction; however, their performance in Pacific Islander populations-comprising only 0.002% of genome-wide association study (GWAS) participants as of 2024-remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TGs), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGSs from Graham et al. and Kanoni et al. multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel, and performance was assessed via incremental R2 from linear mixed models with bootstrapped confidence intervals. HDL-C showed the highest performance (incremental R2 5.0%-15.0%), followed by TC (5.0%-10.7%), LDL-C (5.7%-8.6%), and TG (3.5%-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6%-99.7% variant matching), while a curated pruning-and-thresholding score achieved ∼9% matching and near-zero performance. These findings establish systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.

Pacific Islanders↗

PubMed2026

Meta-analysis of over 8,000 individuals from Hawai'i and Samoa for genetic associations to cardiometabolic phenotypes.

Although genome-wide association studies (GWAS) now routinely reveal genetic associations and biological insights in millions of individuals, underrepresentation of global populations, such as those from Polynesia, continue to persist. These exclusions, often driven by logistical challenges and lack of data, prevent systematic identification of population-enriched associations, such as the association of the missense variant at the CREBRF locus to BMI and type 2 diabetes discovered commonly occurring in Polynesian populations due to its rarity in global populations. Armed with the recently updated TOPMed imputation panel that could benefit studies in diverse populations that previously had poorer imputation performance, we performed the first GWAS of Native Hawaiians and largest to date of Polynesian-ancestry populations (combined N up to 8,461) to identify population-enriched associations for 13 adiposity and cardiometabolic traits available across both cohorts: BMI, fasting glucose, fasting insulin, HDL, height, hip circumference, HOMA-IR, LDL, T2D, total cholesterol, triglycerides, waist circumference, and waist-hip ratio. We found 25 trait-loci associations that met genome-wide significance: 20 previously reported or known associations and 5 associations newly confirmed via meta-analysis. In particular, with improved statistical power, we were able to confirm the suspected association between the missense CREBRF variant with fasting glucose levels. The remaining 4 potentially novel loci-trait associations for BMI, LDL, and waist-hip ratio, however, were not replicated in multi-ethnic datasets from All-of-Us despite having reasonable power to replicate. The lack of Polynesian-enriched findings outside of the CREBRF locus informs the bounds of the effect sizes or frequency of any enriched variants, and suggests that further expansion of cohort sizes from this region of the world and improved imputation references specific to these populations are needed to identify more population-enriched associations.

Journal Article↗