Biology subjects

McGarvey, S. T.

Publications and source records attributed to McGarvey, S. T..

6 recordsLinked to original sources

bioRxiv2021

A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress

Obesity and diabetes have strong heritable components, yet the genetic contributions to these diseases remain largely unexplained. In humans, a missense variant in Creb3 regulatory factor (CREBRF) [rs373863828 (p.Arg457Gln); CREBRFR457Q] is strongly associated with increased odds of obesity but decreased odds of diabetes. Although virtually nothing is known about CREBRFs mechanism of action, emerging evidence implicates it in the adaptive transcriptional response to nutritional stress downstream of TORC1. The objectives of this study were to generate a murine model with knockin of the orthologous variant in mice (CREBRFR458Q) and to test the hypothesis that this CREBRF variant promotes obesity and protects against diabetes by regulating energy and glucose homeostasis downstream of TORC1. To test this hypothesis, we performed extensive phenotypic analysis of CREBRFR458Q knockin mice at baseline and in response to acute (fasting/refeeding), chronic (low- and high-fat diet feeding), and extreme (prolonged fasting) nutritional stress as well as with pharmacological TORC1 inhibition. The results demonstrate that the murine CREBRFR458Q model of the human CREBRFR457Q variant does not influence energy/glucose homeostasis in response to these interventions. Alternative preclinical models and/or studies in humans will be required to decipher the mechanisms linking this variant to human health and disease.

genetics↗

bioRxiv2019

Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2-4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed Clonal Hematopoiesis of Indeterminate Potential (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

genomics↗

bioRxiv2019

Biological Pathways and Gene Networks Link Inflammation and Vascular Remodeling to Both Heart Failure with Preserved and Reduced Ejection Fraction in Women across Ethnicities

IntroductionHeart failure (HF) is understudied among women; especially, genomic evidence implicating shared or unique mechanisms of HF with respect to reduced or preserved ejection fraction (HFrEF, HFpEF) is lacking across ethnic populations of women. Prior genome-wide association studies (GWAS) have identified approximately 30 suggestive genetic variants for HF, although none have been specifically linked to HFrEF or HFpEF.\n\nObjectivesWe aimed to define, replicate, and annotate genetic variants to HFrEF, HFpEF, or both, as well as to investigate potential biological mechanisms underlying HFrEF and HFpEF among African American (AA) and European American (EA) women in three well-characterized, high-quality prospective cohorts, the Womens Health Initiative (WHI) study, the Jackson Heart Study (JHS), and the Framingham Heart Study (FHS).\n\nMethodsGWAS analysis on HFrEF and HFpEF were first performed among 7,982 AA and 4,133 EA in the WHI, followed by pathway analysis employing two independent methodological platforms (GSA-SNP and Mergeomics) curating KEGG, Reactome, and BioCarta pathway databases. GWAS signals and biological pathways identified using the WHI were replicated in the JHS and FHS. For all replicated pathways, we performed cross-phenotype and cross-ethnicity validation analyses to examine shared pathways between HFrEF and HFpEF, and phenotype-specific pathways, across ethnicities. We further prioritized key driver genes for HF according to specific pathways identified.\n\nResultsWe validated one previously reported genetic locus and identified six new ones, among which one locus was allocated to HFrEF and five to HFpEF. Additionally, we defined five biological pathways shared between HFrEF and HFpEF and discovered six HFpEF-specific pathways. These pathways overlapped in two main domains for molecular signaling: 1) inflammation and 2) vascular remodeling (including angiogenesis and vascular patterning), involving key driver genes from collagen and HLA gene families.\n\nConclusionsOur network analysis of three large prospective cohorts of women in the United States defined several novel loci for HF and its subtypes. In particular, several key driver genes reinforce the mechanistic role of inflammation and vascular remodeling in the development of HF, especially HFpEF. Given that therapeutic strategies developed for left ventricular dysfunction have had limited success for HFpEF, several new targets and pathways identified and validated in this study should be further assessed in risk stratification as well as the design of potential new HF interventions.

genetics↗

bioRxiv2019

A missense variant in CREBRF is associated with taller stature in Samoans

ObjectivesStudies have demonstrated that rs373863828, a missense mutation in CREBRF, is associated with a number of anthropometric traits including body mass index (BMI), obesity, percent body fat, hip circumference, and abdominal circumference. Given the biological relationship between height and adiposity, we hypothesized that the effect of this variant on BMI might be due in part to a previously untested association of this variant with height.\n\nMethodsWe tested the hypothesis that minor allele of rs373863828 is associated with height in a Samoan population in two adult cohorts and in a separate cohort of children (age 5 - 18 years old) using linear mixed modeling.\n\nResultsWe found evidence of a strong relationship between rs373863828 and greater mean height in Samoan adults (0.77 cm greater average height for each copy of the minor allele) with the same direction of effect in Samoan children.\n\nConclusionsThese results suggest that the missense variant rs373863828 in CREBRF, first identified through an association with larger BMI, may be related to an underlying biological mechanism affecting overall body size including stature.

genetics↗

bioRxiv2018

Genome-wide association studies in Samoans give insight into the genetic etiology of fasting serum lipid levels.

The current understanding of the genetic architecture of lipids has largely come from genome-wide association studies. To date, few studies have examined the genetic architecture of lipids in Polynesians, and none have in Samoans, whose unique population history, including many population bottlenecks, may provide insight into the biological foundations of variation in lipid levels. Here we performed a genome-wide association study of four fasting serum lipid levels: total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) in a sample of 2,849 Samoans, with validation genotyping for associations in a replication cohort comprising 1,798 Samoans and American Samoans. We identified multiple genome-wide significant associations (P < 5 x 10-8) previously seen in other populations - APOA1 with TG, CETP with HDL, and APOE with TC and LDL - and several suggestive associations (P < 1 x 10-5), including an association of variants downstream of MGAT1 and RAB21 with HDL. However, we observed different association signals for variants near APOE than what has been previously reported in non-Polynesian populations. The association with several known lipid loci combined with the newly-identified associations with variants near MGAT1 and RAB21 suggest that while some of the genetic architecture of lipids is shared between Samoans and other populations, part of the genetic architecture may be Polynesian-specific.

genetics↗

bioRxiv2017

Discordant association of the CREBRF rs373863828 minor allele with increased body mass index and protection from type 2 diabetes in Maori and Pacific (Polynesian) people living in New Zealand

Aim/HypothesesThe minor allele of CREBRF rs373863828 associates with increased body mass index (BMI) and reduced risk of type 2 diabetes (T2D) in the Samoan population of Samoa and American Samoa. Our aim was to test rs373863828 for association with BMI and odds of T2D, gout and chronic kidney disease (CKD) in M[a]ori and Pacific (Polynesian) people living in Aotearoa New Zealand in 2,286 adults.\n\nMethodsAssociation analyses were performed by linear and logistic regression with BMI, log-transformed BMI, waist circumference, T2D, gout and CKD. Analyses were adjusted for age, sex, the first four genome-wide principal components, and (when appropriate) BMI, waist circumference and T2D.\n\nResultsFor the minor allele of rs373863828 the effect size for log-transformed BMI was 0.038 (95% CI [0.022-0.055], P=4.8x10-6) and for T2D was OR=0.59 (95% CI [0.47-0.73], P=1.9x10-6). There was no evidence for association of genotype with variance in BMI (P=0.13). Nor was there evidence for association with serum urate ({beta}=0.012 mmol/L, Pc=0.10), gout (OR=1.00, P=0.98) or CKD (OR=0.91, P=0.59).\n\nConclusions/interpretationOur results replicated, with very similar effect sizes, association of the minor allele of rs373863828 with higher BMI but lower odds of T2D among New Zealand Polynesian adults, as in Samoan adults living in Samoa and American Samoa.

genetics↗