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 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.

Public Health Relevance

RNA sequencing is a method to measure how much each gene within humans are being expressed. Gene expression may differ among tissues, such as different parts of the brain. We are proposing to measure gene expression in brains donated upon death by participants of the Framingham Heart Study, the Religious Orders Study, and the Memory and Aging Project who have been examined regularly for up to 60 years. We propose to compare if gene expression differs across two specific brain regions and to determine if gene expression is associated with whether or not the participants were consistently obese over many years or consistently normal weight. This study will help understand the genetic basis of obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Hyde, James F
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Boston University
Biostatistics & Other Math Sci
Schools of Public Health
United States
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Wake, Christian; Labadorf, Adam; Dumitriu, Alexandra et al. (2016) Novel microRNA discovery using small RNA sequencing in post-mortem human brain. BMC Genomics 17:776