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Title: Ancestry-specific polygenic scores and SNP heritability of 25(OH)D in African- and European-ancestry populations

Author
item HATCHELL, KATHRYN - UNIVERSITY OF WISCONSIN
item LU, QIONGSHI - UNIVERSITY OF WISCONSIN
item HEBBRING, SCOTT - MARSHFIELD CLINIC RESEARCH
item MICHOS, ERIN - JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
item WOOD, ALEXIS - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item ENGELMAN, CORINNE - UNIVERSITY OF WISCONSIN

Submitted to: Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/21/2019
Publication Date: 7/24/2019
Citation: Hatchell, K.E., Lu, Q., Hebbring, S.J., Michos, E.D., Wood, A.C., Engelman, C.D. 2019. Ancestry-specific polygenic scores and SNP heritability of 25(OH)D in African- and European-ancestry populations. Human Genetics. https://doi.org/10.1007/s00439-019-02049-x.
DOI: https://doi.org/10.1007/s00439-019-02049-x

Interpretive Summary: The development of obesity is often preceded by Vitamin D inadequacy, which affects around 50% of adults in the United States. If we can identify who is at risk of Vitamin D inadequacy, we may be able to better predict who will develop obesity and implement prevention strategies. We may also be able to treat the vitamin D inadequacy and therefore prevent the development of obesity for some individuals. We know that Vitamin D levels in the blood are influenced by genetic differences, but only a small portion of the genetic factors contributing to Vitamin D levels have been discovered. To address this need, we reanalyzed data on approximately 12,000 individuals of African- and European-ancestry living in the United States. We conformed some genetic variants known to contribute to Vitamin D levels, but also identified a new set of genetic variants which contribute to Vitamin D levels. Some of these Vitamin D associated variants were similar between the different ancestry groups, but some were specific to either ancestry. When combined into an overall risk score for each group, those with the highest genetic risk had blood level of Vitamin D which were 2.8-3.0 ng/ml lower than those with lowest genetic risk, meaning that these individuals would require an additional 467 to 500 IU of vitamin D intake to maintain levels which reduced the effect of their genetic risk. This information could be useful for clinicians who treat vitamin D deficiency, and for individuals who have relatives with low vitamin D levels, who wish to normalize their levels and reduce their risk of obesity.

Technical Abstract: Vitamin D inadequacy, assessed by 25-hydroxyvitamin D [25(OH)D], affects around 50% of adults in the United States and is associated with numerous adverse health outcomes. Blood 25(OH)D concentrations are influenced by genetic factors that may determine how much vitamin D intake is required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a small portion of the genetic factors contributing to differences in 25(OH)D has been discovered. Therefore, knowledge of a fuller set of genetic factors could be useful for risk prediction of 25(OH)D inadequacy, personalized vitamin D supplementation, and prevention of downstream morbidity and mortality. Using PRSice and weights from published African- and European-ancestry GWAS summary statistics, ancestry-specific polygenic scores (PGSs) were created to capture a more complete set of genetic factors in those of European (n=9569) or African ancestry (n=2761) from three cohort studies. The PGS for African ancestry was derived using all input SNPs (a p value cutoff of 1.0) and had an R**2 of 0.3%; for European ancestry, the optimal PGS used a p value cutoff of 3.5X10**-4 in the target/tuning dataset and had an R**2 of 1.0% in the validation cohort. Those with highest genetic risk had 25(OH)D that was 2.8-3.0 ng/mL lower than those with lowest genetic risk (p=0.0463-3.2X10**-13), requiring an additional 467-500 IU of vitamin D intake to maintain equivalent 25(OH)D. PGSs are a powerful predictive tool that could be leveraged for personalized vitamin D supplementation to prevent the negative downstream effects of 25(OH)D inadequacy.