Small-group originating model: Optimized individual-level GWAS simulation featured by SLiM and using open-access data.

The development of analytical methods for Genome-wide Association Studies (GWAS) has outpaced the evolution of simulation techniques and pipelines. This disparity underscores the importance of innovative simulation methods that can keep pace with the rapidly increasing scale of GWAS. The median sample size of GWAS over the past ten years has exceeded 50,000 individuals, a trend that emphasizes the need for simulation tools capable of generating data on a similar or larger scale. This paper introduces a novel method, the small-group originating (SGO) model, utilizing the SLiM software for simulating individual-level GWAS data. Our standardized protocol facilitates the generation of tens of thousands of pseudo-individuals with millions of variants from small (30-90) open-access datasets. SGO stands out, especially when compared to the widely-used resampling method in HapGen, showcasing superior simulation efficiency for large sample sizes (> 13,000) of unrelated individuals. This capability is particularly relevant given the current trajectory towards larger GWAS, necessitating tools that can simulate datasets reflective of this growth. Additionally, SGO provides customization options and can model dynamic life cycles and mating across generations, positioning it as a highly promising alternative for GWAS simulations. In a case study, sensitivity analyses of chromosome-level principal component analysis and kinship coefficient estimation were conducted. The results highlighted the poor robustness of chromosome-level quality control (QC) indexes and the uneven distribution of population structure across chromosomes and ancestries, advocating for the caution against relying solely on chromosome-level QC statistics. With its flexible and efficient approach to generating pseudo GWAS data, our standardized SGO protocol emerges as a crucial asset for method development, power analysis, and benchmarking in GWAS research. It is especially vital in the context of accommodating the demands for large-scale simulations, aligning with the current and future scale of GWAS.

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.