Obesity Brain Expression

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Neuroendocrine factors have been convincingly implicated in the etiology of obesity. Although genome-wide association studies (GWAS), have identified scores of genes and loci associated with obesity, insight into the functional roles for these genes, particularly within the human brain, is lacking. Many brain banks do not have a single body mass index (BMI) measure. However, brain donation programs within longitudinal, cohort studies represent a unique resource of brain samples with up to six decades of ante-mortem data including BMI. This proposal is a collaboration among three such longitudinal cohort studies: 1) The Framingham Heart Study (FHS) 2) The Religious Order Study (ROS) and 3) the Memory and Aging Project (MAP). Selection from over 1,300 post mortem brain samples already donated via these studies enabled identification of 75 samples from consistently obese individuals and 75 samples from individuals with consistently normal BMI (18.5<BMI<25). These carefully selected samples provide an unprecedented opportunity to study the relationship of gene expression in specific brain regions to BMI providing key insight into the neuroendocrine control of BMI. This application proposes to apply next generation RNA sequencing and microRNA sequencing technology and state of the art statistical approaches in highly characterized, selected samples from the FHS, ROS and MAP brain banks to further the understanding of the genetic basis of obesity. The return on investment in generating these data will be maximized by creating a publicly available resource of extensive brain derived genomic data of value for studying a wide range of diseases and clinical measures. In Aim 1 we propose RNA and microRNA sequencing in 2 brain regions: lateral hypothalamus and striatum to determine region specific gene expression patterns in 75 samples from consistently obese individuals and 75 controls (consistently normal BMI). RNA-sequencing will identify coding sequence variants, novel gene transcripts, & splice junctions and estimate brain region specific RNA expression levels for individual exons of genes. MicroRNA sequencing will identify short RNA sequences implicated in regulation of gene expression. We will use these data to characterize genes previously identified in genomewide association studies and to identify novel genes differentially expressed between brain tissue from obese and non-obese individuals. In Aim 2 we will integrate the genome-wide SNP and transcriptome data to perform eSNP, eQTL, and pathway analyses to identify underlying biological mechanisms. These studies will provide insight into the role of genes in the initiation and pathophysiology of obesity and create a valuable public database containing comprehensively characterized regional gene expression in brain in a cohort of comprehensively phenotypically characterized participants.