Biology subjects

Klarin, D.

Publications and source records attributed to Klarin, D..

5 recordsLinked to original sources

bioRxiv2021

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

genomics↗

bioRxiv2019

Assessing a causal relationship between circulating lipids and breast cancer risk via Mendelian randomization

ObjectiveTo assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein cholesterol, HDL; low-density lipoprotein cholesterol, LDL; triglycerides, TG) with risk for breast cancer.\n\nDesignMendelian randomization (MR) study.\n\nSetting and ParticipantsData from genome-wide association studies in up to 215,551 subjects from the Million Veterans Project were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on breast cancer risk was evaluated using genetic data from the BCAC consortium based on 122,977 breast cancer cases and 105,974 controls.\n\nExposuresGenetically modified plasma levels of LDL, HDL, or TG.\n\nMain Outcomes and MeasuresOdds ratio (OR) for breast cancer risk per standard-deviation increase in HDL, LDL, or TG.\n\nResultsWe observed that a 1-SD genetically determined increase in HDL levels is associated with an increased risk for all breast cancers (HDL: OR=1.08, 95% CI=1.04-1.13, P=7.4x10-5).\n\nMultivariable MR analysis, which adjusted for the effects of LDL, TG, body mass index, and age at menarche, corroborated this observation for HDL (OR=1.06, 95% CI=1.03-1.10, P=4.9x10-4) and also a relationship between LDL and breast cancer risk (OR=1.03, 95% CI=1.01-1.07, P=0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for breast cancers (OR=1.11, 95% CI=1.06-1.16, P=1.5x10-6), including gene-specific associations at ABCA1, APOE-APOC1-APOC4-APOC2 and CETP. In addition, we find evidence that genetic variation at the ABO locus affects both lipid levels and breast cancer.\n\nConclusionsGenetically elevated plasma HDL levels appear to increase breast cancer risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal to develop potential therapeutic strategies aimed at altering the HDL-mediated effect on breast cancer risk.

genomics↗

bioRxiv2019

Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

Although alcohol consumption level and alcohol use disorder (AUD) diagnosis are both moderately heritable, their genetic risks and overlap are not well understood. We conducted genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (reflecting alcohol consumption) and AUD diagnoses from electronic health records (EHRs) in a single, large multi-ancestry Million Veteran Program sample. Meta-analysis across population groups (N = 274,424) identified 18 genome-wide significant loci, 5 of which were associated with both traits and 13 with either AUDIT-C (N = 8) or AUD (N = 5). A significant genetic correlation between the traits reflects this overlap. However, downstream analyses revealed biologically meaningful points of divergence. Cell-type group partitioning heritability enrichment analyses indicated that central nervous system was the most significant cell type for AUDIT-C and the only significant cell type for AUD. Polygenic risk scores (PRS) for both traits were associated with alcohol-related disorders in two independent samples. Genetic correlations for 188 non-alcohol-related traits were significantly different for the two traits, as were the phenotypes associated with the traits polygenic risk scores. We conclude that EHR-derived, longitudinal, repeated measures of alcohol consumption level and AUD diagnosis can facilitate genetic discovery and help to elucidate the relationship between drinking level and AUD risk. Finally, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

genetics↗

bioRxiv2018

Genetic association of photoplethysmography-derived arterial stiffness index with blood pressure and coronary artery disease

BackgroundArterial stiffness index (ASI) is independently associated with blood pressure and coronary artery disease (CAD) in epidemiologic studies. However, it is unknown whether these associations represent causal relationships.\n\nObjectivesHere, we assess whether genetic predisposition to increased ASI is associated with elevated blood pressure and CAD risk.\n\nMethodsGenome-wide association analysis (GWAS) of finger photoplethysmography-derived ASI was performed in 131,686 participants from the UK Biobank. Across UK Biobank participants not in the ASI GWAS, a 6-variant ASI polygenic risk score was calculated. The ASI polygenic score was associated with systolic and diastolic blood pressures (SBP, DBP, N=208,897), and with incident CAD over 10 years follow-up (N=223,061; 7,534 cases). The lack of CAD association observed was replicated among 184,305 participants (60,810 cases) from the Coronary Artery Disease Genetics Consortium (CARDIOGRAMplusC4D).\n\nResultsWe replicated prior reports of the epidemiologic association of ASI with SBP (Beta 0.55mmHg, [95% CI, 0.45-0.65], P=5.77x10-24), DBP (Beta 1.05mmHg, [95% CI, 0.99-1.11], P=7.27x10-272), and incident CAD (HR 1.08 [95% CI, 1.04-1.11], P=1.5x10-6) in multivariable models. While each SD increase in genetic predisposition to elevated ASI was highly associated with SBP (Beta 4.63 mmHg [95% CI, 2.1-7.2]; P=3.37x10-4), and DBP (Beta 2.61 mmHg [95% CI, 1.2-4.0]; P=2.85x10-4), no association was observed with incident CAD in UK Biobank (HR 1.12 [95% CI, 0.55-2.3]; P=0.75), or with prevalent CAD in CARDIOGRAMplusC4D (OR 0.56 [95% CI, 0.26-1.24]; P=0.15).\n\nConclusionsA genetic predisposition to higher ASI was associated with elevated blood pressure but not with increased risk of developing CAD.\n\nCondensed AbstractArterial stiffness index (ASI) is proposed by some as a surrogate of blood pressure and coronary artery disease (CAD) risk based on epidemiologic analyses. We tested whether genetic predisposition to increased ASI is associated with elevated blood pressure and CAD risk to assess whether these represent causal relationships. We find that a genetic predisposition to higher ASI is associated with elevated systolic (Beta 4.63 mmHg [95% CI, 2.1-7.2]) and diastolic blood pressures (Beta 2.61 mmHg [95% CI, 1.2-4.0]) in the UK Biobank, but not associated with incident CAD in the UK Biobank (P=0.75) or with prevalent CAD in CARDIOGRAMplusC4D (P=0.15). These data support a causal relationship of ASI with blood pressure but do not support the notion that ASI is a suitable surrogate for CAD risk.

bioinformatics↗

bioRxiv2017

Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

Identification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases - breast cancer and severe obesity.\n\nOne Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

genomics↗