Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations

Hebbring

et al. 2019

Preprint

Short title: Ancestry-specific 25(OH)D PGS and SNP heritability 17 18 Precis: Ancestry-specific polygenic risk scores for 25(OH)D capture more genetic variance than do 19 previous GWAS findings and could be leveraged to inform personalized vitamin D supplementation 20 21 Word Count: 4,965 22 23 Abstract: 41 Context. Vitamin D inadequacy, assessed by 25-hydroxyvitamin D [25(OH)D], affects around 50% of 42 adults in the United States and is associated with numerous adverse health outcomes. Blood 25(OH)D 43 concentrations are influenced by genetic factors that may determine how much vitamin D intake is 44 required to reach optimal 25(OH)D. Despite large genome-wide association studies (GWASs), only a 45 small portion of the genetic factors contributing to differences in 25(OH)D levels has been discovered.46 Objective. Therefore, knowledge of a fuller set of genetic factors could be useful for risk prediction of 47 25(OH)D inadequacy, personalized vitamin D supplementation, and prevention of morbidity and mortality 48 from deficient 25(OH)D. 49Design. Using PRSice and weights from published African-and European-ancestry GWAS summary 50 statistics, ancestry-specific polygenic scores (PGSs) were created to capture a more complete set of 51 genetic factors. 52Patients or Other Participants. Participants (European ancestry n=9,569, African ancestry n=2,761) 53 came from three cohort studies. 54Main Outcome Measure(s). Blood concentrations of 25(OH)D. 55Results. The PGS for African ancestry was derived using all input SNPs (a p-value cut-off of 1.0) and 56 had an R 2 of 0.3%; for European ancestry, the optimal PGS used a p-value cut-off of 3.5x10 -4 in the 57 target/tuning dataset and had an R 2 of 1.0% in the validation cohort. Those with highest genetic risk had 58 25(OH)D that was 2.8-3.0 ng/ml lower than those with lowest genetic risk (p=0.0463 to 3.2x10 -13 ), 59requiring an additional 467 to 500 IU of vitamin D intake to maintain equivalent 25(OH)D. 60Conclusions. PGSs are a powerful predictive tool that could be leveraged for personalized vitamin D 61 supplementation to prevent the negative downstream effects of 25(OH)D inadequacy. 62 63 64 65 Keywords: Genetics, ancestry, vitamin D, diet, polygenic risk score, heritability higher prevalence in those with darker skin tones (1-3). Observational studies show associations between 71 low vitamin D concentrations and numerous adverse health outcomes, including autoimmune diseases, 72 migraines, hypertension, dyslipidemia, cardiovascular events, and cardiovascular mortality (1,3-9). These73 studies are supported by recent Mendelian randomization studies which provide evidence for a causal 74 relationship between low vitamin D concentrations and increased risk of obesity, ovarian cancer, 75 hypertension, lower cognitive function during aging, multiple sclerosis, and all cause and cancer mortality 76 (10-16). Furthermore, some clinical trials have shown that vitamin D and calcium supplementation are 77 important in the prevention of fractures and cardiovascular risk factor...

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Hebbring

et al. 2019

Preprint

“…Previously, an optimal PGS was determined in an ancestry-specific manner for those of European or African ancestries (29). PGSs were weighted using effect sizes from an independent multi-ethnic GWAS, TRANSCEN-D, the largest multi-ethnic vitamin D GWAS meta-analysis to date (40). European summary statistics came from the SUNLIGHT discovery cohort that was included in TRANSCEN-D. After QC, 8,569 European samples and 1,099 African-ancestry samples remained for the analysis.…”

Section: Methodsmentioning

confidence: 99%

Multi-ethnic analysis shows genetic risk and environmental predictors interact to influence 25(OH)D concentration and optimal vitamin D intake

Mares

et al. 2019

Preprint

BackgroundVitamin D inadequacy affects almost 50% of adults in the United States and is associated with numerous adverse health effects. Vitamin D concentration [25(OH)D] is a complex trait with genetic and environmental predictors that work in tandem to influence 25(OH)D and may determine how much vitamin D intake is required to reach an optimal 25(OH)D concentration. To date, there has been little investigation into how genetics and environment interact to affect 25(OH)D.ObjectiveInteractions between continuous measures of a polygenic score (PGS) and vitamin D intake (PGS*intake) or available ultra-violet (UV) radiation (PGS*UV) were evaluated separately in individuals of African or European ancestry.MethodsMega-analyses were performed using three independent cohorts (N=9,668; African ancestry n=1,099; European ancestry n=8,569). Interaction terms and joint effects (main and interaction terms) were tested using one-degree of freedom (DF) and 2-DF models, respectively. All models controlled for age, sex, body mass index (BMI), cohort, and dietary intake/available UV. Additionally, in participants achieving Institute of Medicine (IOM) vitamin D intake recommendations, 25(OH)D was evaluated by level of genetic risk of 25(OH)D deficiency.ResultsThe 2-DF PGS*intake, 1-DF PGS*UV and 2-DF PGS*UV results were statistically significant in participants of European ancestry (p=3.3×10−18, 2.1×10−2, and 2.4×10−19, respectively), but not in those of African ancestry. In European-ancestry participants who reached IOM vitamin D intake guidelines, the percent of participants achieving adequate 25(OH)D (>20ng/ml) increased as genetic risk decreased (72% vs 89% in the highest vs lowest risk categories; p=0.018).ConclusionsAvailable UV radiation and vitamin D intake interact with genetics to influence 25(OH)D. Individuals with higher genetic risk of deficiency may require more vitamin D exposure to maintain optimal 25(OH)D concentrations. Overall, the results showcase the importance of incorporating both environmental and genetic factors into analyses, as well as the potential for gene-environment interactions to inform personalized dosing of vitamin D.Sources of SupportARICThe Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The authors thank the staff and participants of the ARIC study for their important contributions.Funding for GENEVA was provided by National Human Genome Research Institute grant U01HG004402 (E. Boerwinkle).MESAMESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491.The MESA CARe data used for the analyses described in this manuscript were obtained through Genetics (accession numbers). Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226.Funding support for the Vitamin D dataset was provided by grant HL096875WHIThe WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI.WHI PAGE is funded through the NHGRI Population Architecture Using Genomics and Epidemiology (PAGE) network (Grant Number U01 HG004790). Assistance with phenotype harmonization, SNP selection, data cleaning, meta-analyses, data management and dissemination, and general study coordination, was provided by the PAGE Coordinating Center (U01HG004801-01).Funding support for WHI GARNET was provided through the NHGRI Genomics and Randomized Trials Network (GARNET) (Grant Number U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH Genes, Environment and Health Initiative [GEI] (U01 HG004424). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGa Paccession phs000200.v11.p3.Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278.OtherKEH was supported by an NLM training grant to the Computation and Informatics in Biology and Medicine Training Program (NLM 5T15LM007359). Computational resources were supported by a core grant to the Center for Demography and Ecology at the University of Wisconsin-Madison (P2C HD047873).JM was supported by the Department of Ophthalmology and Visual Sciences, and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences from the Research to Prevent Blindness, and by National Institutes of Health, National Eye Institute grants R01 EY016686, R01 EY025292.

“…Previously, an optimal genome-wide PGS was determined in an ancestry-specific manner for those of European or African ancestries (Hatchell et al, 2019). PGSs were weighted using effect sizes from an independent multiethnic GWAS, TRANSCEN-D, the largest multiethnic vitamin D GWAS meta-analysis to date (Hong et al, 2018). European summary statistics came from the SUNLIGHT discovery cohort that was included in TRANSCEN-D. After QC, 8,569 European samples and 1,099 African-ancestry samples remained for the analysis.…”

Section: Data Quality Controlmentioning

confidence: 99%

Multi‐ethnic analysis shows genetic risk and environmental predictors interact to influence 25(OH)D concentration and optimal vitamin D intake

Mares

et al. 2019

Genetic Epidemiology

25‐Hydroxyvitamin D (25(OH)D) concentration is a complex trait with genetic and environmental predictors that may determine how much vitamin D exposure is required to reach optimal concentration. Interactions between continuous measures of a polygenic score (PGS) and vitamin D intake (PGS*intake) or available ultraviolet (UV) radiation (PGS*UV) were evaluated in individuals of African (n = 1,099) or European (n = 8,569) ancestries. Interaction terms and joint effects (main and interaction terms) were tested using one‐degree of freedom (1‐DF) and 2‐DF models, respectively. Models controlled for age, sex, body mass index, cohort, and dietary intake/available UV. In addition, in participants achieving Institute of Medicine (IOM) vitamin D intake recommendations, 25(OH)D was evaluated by level PGS. The 2‐DF PGS*intake, 1‐DF PGS*UV, and 2‐DF PGS*UV results were statistically significant in participants of European ancestry (p = 3.3 × 10−18, p = 2.1 × 10−2, and p = 2.4 × 10−19, respectively), but not in those of African ancestry. In European‐ancestry participants reaching IOM vitamin D intake guidelines, the percent of participants achieving adequate 25(OH)D ( >20 ng/ml) increased as genetic risk decreased (72% vs. 89% in highest vs. lowest risk; p = .018). Available UV radiation and vitamin D intake interact with genetics to influence 25(OH)D. Individuals with higher genetic risk may require more vitamin D exposure to maintain optimal 25(OH)D concentrations.