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Investigation of Adiposity Phenotypes in AA Associated with GALNT10 & Related Pathway Genes

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Investigation of Adiposity Phenotypes in AA Associated with GALNT10 & Related Pathway Genes Investigation of Adiposity Phenotypes in AA Associated With GALNT10 & Related Pathway Genes By Mary E. Stromberg A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY In Molecular Genetics and Genomics December 2018 Winston-Salem, North Carolina Approved by: Donald W. Bowden, Ph.D., Advisor Maggie C.Y. Ng, Ph.D., Advisor Timothy D. Howard, Ph.D., Chair Swapan Das, Ph.D. John P. Parks, Ph.D. Acknowledgements I would first like to thank my mentors, Dr. Bowden and Dr. Ng, for guiding my learning and growth during my years at Wake Forest University School of Medicine. Thank you Dr. Ng for spending so much time ensuring that I learn every detail of every protocol, and supporting me through personal difficulties over the years. Thank you Dr. Bowden for your guidance in making me a better scientist and person. I would like to thank my committee for their patience and the countless meetings we have had in discussing this project. I would like to say thank you to the members of our lab as well as the Parks lab for their support and friendship as well as their contributions to my project. Special thanks to Dean Godwin for his support and understanding. The umbrella program here at WFU has given me the chance to meet some of the best friends I could have wished for. I would like to also thank those who have taught me along the way and helped me to get to this point of my life, with special thanks to the late Dr. Shakarian, Dr. Wheeler and Dr. MacDonald. Instrumental in my success is my family, and I would like to thank them for their support and encouragement. My parents, brother and sister have encouraged me in difficult times and I could not have triumphed without this encouragement. We have lost multiple family members and seen some severe disease in our family in the last several years, so I would like to also acknowledge the strength and support of my extended family and grandparents during what has been a difficult time in my life. Last but certainly not least, I would like to thank my fiance, David Jacobs, for being my rock and whose companionship has held me together over the course of our relationship. His family has been supportive and encouraging towards me and towards us for the entirety of our relationship, and this has been very important to me and has allowed me to focus ii on my degree during overly difficult times, and I could not have found a better family to join. Thank you, everyone. iii Table of Contents Page List of Figures and Tables iv List of Abbreviations vi Abstract 1 Chapter 1: Introduction 4 Chapter 2: High Density Investigation of GALNT10 Locus In Association with Adiposity Phenotypes in African Americans 22 Chapter 3: GALNT10-related metabolic pathway genes and their association with BMI 44 Chapter 4: Investigation of Obesity Phenotypes in Mouse Knockout Model for GALNT10 67 Chapter 5: Discussion and Conclusions 100 References 109 Scholastic Vita 119 iv List of Figures and Tables Page Chapter 2 Table 1. Study Sample Characteristics 39 Table 2. GALNT10 Association with Body Mass Index 40 Table 3. GALNT10 Association with Adiposity Traits 41 Table 4. eQTL in GALNT10 Region 42 Table 5. SNAP LD Calculation 43 Chapter 3 Table 1. Study Sample Characteristics 59 Figure 1. Pathway Details 59 Table 2: Meta analysis Results for Association with BMI in AA 61 Supplementary Table 1. Genes Tested for Association by Pathway 63 Chapter 4 Figure 1. Experimentation Timeline 82 Table 1: Body Weight Weekly 83 Figure 2. Body Weight Data 85 v Table 2: Glucose Tolerance Test Baseline 86 Table 3: Glucose Tolerance Test Week 12 87 Figure 3. Glucose Tolerance Test Results 88 Table 4. Insulin Level at Baseline 89 Figure 4. Insulin Level at Baseline 89 Table 5: Insulin Tolerance Test Results Week 12 90 Figure 5: Insulin Tolerance Test Results Week 12 91 Table 6. Necropsy Measures 91 Figure 6. Necropsy Measures 92 Table 7. Cholesterol composition at necropsy 93 Figure 7. Cholesterol composition at necropsy 94 Table 8. Triglyceride Levels at each blood draw. 95 Figure 8. Triglyceride Levels at each blood draw. 95 Figure 9. Histology Samples 96 Table 9. Histological results of fat depot composition at necropsy 98 Figure 10. Histological results of fat depot composition at necropsy 99 vi List of Abbreviations AA African American AFR African population in 1000 Genomes AMPK Protein kinase AMP-activated catalytic subunit alpha 1 AUC Area under the curve BDNF Brain-derived neutrophic factor BMI Body-mass index BW Body Weight CDC Centers for Disease Control CERS2 Ceramide synthase 2 CHD Coronary heart disease cm Centimeters CNS Central nervous system CT Computed tomography scan DAVID Database for Annotation, Visualization and Integrated Discovery DEXA Dual energy X-ray absorptiometry DNA Deoxyribonucleic acid EAF Effect allele frequency eQTL Expression quantitative trait locus ES Embryonic stem cell ESRD End-stage renal disease vii EVS Exome variant server FG Fasting glucose FI Fasting insulin FTO Alpha-ketoglutarate dependant dioxygenase GalNac N-acetyl galactose GALNT10 N-acetyl galactosaminyl transferase GMMAT Generalized Linear Mixed Model Association Test GonFat Gonadal Fat GRM Genetic relationship matrix GT Genotype GTT Glucose Tolerance Test GWAS Genome-wide association study HDL High density lipoprotein HWE Hardy-Weinberg Equilibrium IP Intraperitoneal IRASFS Insulin Resistance Atherosclerosis Family Study ITT Insulin tolerance test kg Kilogram KO Knock-out LD Linkage disequilibrium LDL Low-density lipoprotein viii LMM Linear Mixed Model LOF Loss-of-function LW Liver weight m2 Meters squared MAF Minor allele frequency MC4R Melanocortin 4 receptor MEGA Multi-ethnic Genotyping Array N Number of subjects NCBI National Center for Biotechnology Information NEFA Non-esterified fatty acid p p value PC Principal Component PC1 Principal Component 1 Pcorr Corrected p value QC Quality control S/T Serine/Threonine SAT Subcutaneous adipose tissue SD Standard deviation SH2B1 SH2B adaptor protein 1 SNAP SNP Annotation and Proxy Search SNP Single nucleotide polymorphism ix T2D, T2DM Type 2 Diabetes Mellitus TC Total cholesterol TG Triglyceride U Units UGCG UDP-glucose ceramide glycosyltransferase µm micrometers VAT Visceral Adipose Tissue VSR Visceral to subcutaneous adipose tissue ratio WAIST Waist circumference WHO World Health Organization WHR Waist to hip ratio WHRadjBMI Waist to hip ratio adjusted for BMI WT Wild-type x Abstract The overall goal of this project is to verify previous findings in the GALNT10 region and to expand our knowledge of this locus via genomic association studies in obesity-related traits, comparison to expression quantitative trait loci (eQTL) data, and a mouse knockout model, in addition to furthering our knowledge of genes in the pathway in which GALNT10 acts. Previously, genome-wide association studies in African Americans (AA) have identified common variants upstream of GALNT10 locus for association with body mass index (BMI). These studies encompassed a small number of variants upstream of GALNT10 that were common, noncoding variants, as is typically seen in GWAS studies. In chapter 2, we first assessed the region of GALNT10 for common, low frequency, coding, and noncoding variants to determine whether the variants used in the GWAS studies were the potentially causal variants for this association with BMI using a multiplatform genetic analysis for association in up to 4,326 AA. We next tested for association of our significant SNPs from the first stage in additional adiposity measures. Thirdly, we compared our significant SNPs from stage 1 with AA eQTL data to determine whether there is any correlation suggesting that our associated region alters the expression of GALNT10 in any way. Stage 1 meta-analysis of our platforms revealed significant associations between BMI and common SNPs such as SNPs rs4569924, rs1428120, rs755123885 and rs11958496 (5.69x10-5<p<8.57x10-5) These SNPs were not shown to be associated with other measures of obesity. eQTL analysis showed 15 eQTLs within the GALNT10 region, although the highest correlation with our most significant SNPs in this region was 0.30 and the reported target gene list does not include GALNT10. Our next goal was to determine whether genes that work in the same pathways as GALNT10 contribute measurably to obesity phenotypes. The GALNT family is known to catalyze the first step in mucin-type O-linked glycosylation, which occurs downstream of ceramide and ganglioside synthesis. We chose to test for association of GALNT family members and genes that work in the ceramide and ganglioside synthesis pathways in order to better understand which genes in this pathway may contribute to polygenic obesity We again utilized our multiplatform genetic analysis design with up to 4,236 AA subjects per platform. Meta-analysis in 8,475 total subjects revealed top BMI-associated variants in GALNT2, GCNT4, GALNT10, NEU1, CD36, GBA2, GALC, ST3GAL2, and GCNT7 (3.57E-03≤Pcorr≤3.26E-02). These genes play key roles in Mucin type O-linked glycosylation and sphingolipid biosynthesis, which are key obesity pathways. Lastly, our goal for chapter 4 was to determine whether a knockout mouse model of GALNT10 confirms our association findings and confers increased weight as well as additional obesity phenotypes. 20 mice were tested over 14 weeks for obesity-related phenotypes. At week 16 on the HFD, mice were necropsied and tissues collected. Adipose tissue was sectioned and stained with hematoxylin & eosin. Slides were studied for number and size of adipocytes present in each fat depot. We were able to measure a significant increase in number of adipocytes in BAT in KO males and females (1.84E-92<p<1.18E-09), in SQ KO females and WT males 2 (2.79E-26<p< p=6E-17), and in gonadal fat in KO females and WT males (6.06E- 68<p<9.48E-29).
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