Genetics

Using omics data, we will elucidate pleiotropic variants that play a role in a number of common traits and diseases with high public health significance, including asthma, adiposity, type 2 diabetes, and blood lipid profiles. We will accomplish this by using a large population sample of 500,000 individuals with genome-wide imputed sequence data, >150,000 subjects with Whole Genome Sequence (WGS) data, and ~950 subjects with gene expression data from 53 tissues and WGS data. We will use statistical methods to detect pleiotropic effects and perform biological validation to better understand the role pleiotropy plays in complex disease etiology.

In addition, using genome-wide genotype and sequence data, we will elucidate pleiotropic variants for Alzheimer’s disease and a number of comorbid phenotypes, such as type 2 diabetes, stroke, blood pressure, adiposity, and blood lipids. We will accomplish this using a large population sample of 500,000 individuals for discovery analyses and almost 23,000 subjects for replication. We will use statistical methods to detect pleiotropic effects to better understand the role pleiotropy plays in complex disease etiology including Alzheimer’s disease.

Principal Investigators:

• Andrew DeWan, PhD, MPH, Associate Professor, Department of Chronic Disease Epidemiology, Director, Yale Center for Perinatal, Pediatric and Environmental Epidemiology; email: andrew.dewan@yale.edu
• Suzanne M. Leal, PhD, Professor of Neurology, Columbia University, Center for Statistical Genetics at The Gertrude H. Sergievsky Center & Department of Neurology; email: sml3@cumc.columbia.edu

To investigate the genetic basis of age-related hearing impairment (ARHI) and tinnitus we will analyze genotype array, whole-genome imputed and exome sequence data from 500,000 participants in the UK Biobank. We will conduct single and rare variant aggregate association tests, testing for main effects, sex, and age-specific associations and interactions (gene x gene; gene x environment; gene x age; gene x age; and gene x sex) controlling for important confounders, e.g. noise exposure.

We will perform fine mapping to tease apart functional causal variants from those which are in linkage disequilibrium. We will also test for pleiotropy and perform mediation analysis to determine if biological or mediated pleiotropy has been detected. We plan to develop novel approaches to analyze imputed genetic data that explicitly account for the uncertainty in genotype calls during association analysis. By ignoring or improperly modeling the uncertainty in imputed genotypes, current methods suffer from a decreased ability to detect associations as well as an increased false positive findings rate. Therefore, we will develop methods to analyze imputed data, which properly models imputed genotype data uncertainty to allow for the detection of associations, interactions, pleiotropy, and fine mapping. The novel methods will be thoroughly evaluated and implemented in our SEQSpark software program to perform data quality control, annotation, and association analysis for hundreds of thousands of samples with imputed genotype data. This study has the potential for significant public health impact by providing a useful analytic tool to the research community and by conducting a well-powered, comprehensive investigation of the genetic etiology of ARHI and tinnitus which in turn will aid in risk prediction, prevention, and improved and new treatment modalities.

Principal Investigators:

• Suzanne M. Leal, PhD, Professor of Neurology, Columbia University, Center for Statistical Genetics at The Gertrude H. Sergievsky Center & Department of Neurology; email: sml3@cumc.columbia.edu
  
• Andrew DeWan, PhD, MPH, Associate Professor, Department of Chronic Disease Epidemiology, Director, Yale Center for Perinatal, Pediatric and Environmental Epidemiology; email: andrew.dewan@yale.edu

Children with substantial African ancestry have long been known to have half or less the rate of acute lymphoblastic leukemia (ALL) than do children with other continental ancestries. Our project will conduct admixture mapping of ALL risk and outcome in African-American patients. The research will potentially answer a long-standing mystery by revealing critical genes or loci that explain the comparative deficit of B-cell ALL in AA compared to EA children, possibly pointing towards prevention.

Principal Investigator (Yale Subaward):

• Andrew DeWan, PhD, MPH, Associate Professor, Chronic Disease Epidemiology, Yale School of Public Health; Director, Yale Center for Perinatal, Pediatric and Environmental Epidemiology email: andrew.dewan@yale.edu
  

Our study of energy metabolism among Samoans in the context of a genetic variant that increases the risk for obesity will help us understand some of the key biological pathways that are affected by this gene variant and influence obesity and related health outcomes. The proposed research is relevant to public health because it will characterize energy metabolic mechanisms contributing to obesity in the context of a novel gene variant. This research is relevant to the NIH mission of advancing the understanding, prevention, and treatment of obesity and heart diseases.

There is a fundamental gap in our understanding of the reasons behind the high prevalence of obesity in Samoa, which is among the highest observed across the globe. Over 80% of Samoan adults are overweight or obese, with severe obesity reaching an alarming 33% in women in American Samoa. In a genome-wide association study, we recently identified a novel missense variant (p.Arg457Gln, minor allele frequency 0.259) in CREB3 Regulatory Factor (CREBRF) that is highly associated with BMI, with an effect size greater than any known common BMI risk variant.

The overall goal of this research project is to gain insight into the metabolic differences responsible for the excess weight gain associated with the CREBRF variant. Based on our observations that overexpression of the missense variant promotes lipid storage and reduces energy substrate oxidation (decreased mitochondrial respiration) in an adipocyte model, our hypothesis is that a lower resting metabolic rate (RMR) is involved. Supporting a relationship between low mitochondrial respiration and low RMR, we recently observed that lower skeletal muscle mitochondrial respiration is associated with lower RMR in African American women (AAW). In addition, we recently demonstrated lower intervention-induced weight loss in AAW compared to Caucasian women due to a lower RMR, leading to lower energy requirements. Based on these observations, and the fact that the majority of genes known to contribute to human obesity do so primarily by influencing the central control of energy intake and/or expenditure, we will determine the role that energy expenditure (EE) and energy intake (EI) play in the increased obesity risk in the Samoan population associated with the CREBRF missense variant.

We are proposing a longitudinal study to define the impact of the variant on energy balance in human subjects with zero, one, or two copies of the risk allele to address three specific aims: 1) to determine the components of EE and substrate metabolism [RMR; TEF, thermic effect of food; total EE; RQ, substrate utilization; and PA, physical activity] using gold standard methods that include doubly-labeled water (DLW), indirect calorimetry, and objective activity monitoring; 2) to determine EI using the gold standard method of DLW intake balance technique; and 3) to determine the relationship between energy metabolism and weight gain by comparing the above energy metabolism parameters and weight gain over 24-36 months. The studies will provide novel, and significant insight into the metabolic differences responsible for the excess weight gain in those with the CREBRF variant, which in turn plays a significant role in the extreme prevalence of obesity in Samoa. This research will advance the understanding, prevention, and appropriate treatment of obesity and heart diseases in this high-risk population.

Principal Investigator (Yale Subaward):

• Nicola Hawley, PhD, Associate Professor, Department of Chronic Diseases; email: nicola.hawley@yale.edu