Neuronal Genes for Subcutaneous Fat Thickness in Human and Pig Are Identified by Local Genomic Sequencing and Combined SNP Association Study

Obesity represents a major global public health problem that increases the risk for cardiovascular or metabolic disease. The pigs represent an exceptional biomedical model related to energy metabolism and obesity in humans. To pinpoint causal genetic factors for a common form of obesity, we conducted local genomic de novo sequencing, 18.2 Mb, of a porcine QTL region affecting fatness traits, and carried out SNP association studies for backfat thickness and intramuscular fat content in pigs. In order to relate the association studies in pigs to human obesity, we performed a targeted genome wide association study for subcutaneous fat thickness in a cohort population of 8,842 Korean individuals. These combined association studies in human and pig revealed a significant SNP located in a gene family with sequence similarity 73, member A (FAM73A) associated with subscapular skin-fold thickness in humans (rs4121165, GC-corrected p-value  = 0.0000175) and with backfat thickness in pigs (ASGA0029495, p-value  = 0.000031). Our combined association studies also suggest that eight neuronal genes are responsible for subcutaneous fat thickness: NEGR1, SLC44A5, PDE4B, LPHN2, ELTD1, ST6GALNAC3, ST6GALNAC5, and TTLL7. These results provide strong support for a major involvement of the CNS in the genetic predisposition to a common form of obesity.

[1]  N. Reinsch,et al.  Parent-of-origin effects cause genetic variation in pig performance traits. , 2010, Animal : an international journal of animal bioscience.

[2]  David Goldman,et al.  Genome-wide association identifies candidate genes that influence the human electroencephalogram , 2010, Proceedings of the National Academy of Sciences.

[3]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[4]  K. Katoh,et al.  Genetic correlations among carcass cross-sectional fat area ratios, production traits, intramuscular fat, and serum leptin concentration in Duroc pigs. , 2009, Journal of animal science.

[5]  W. Gerald,et al.  Genes that mediate breast cancer metastasis to the brain , 2009, Nature.

[6]  J. Hohmann,et al.  Expression Profiling of the Solute Carrier Gene Family in the Mouse Brain , 2009, Journal of Pharmacology and Experimental Therapeutics.

[7]  Taesung Park,et al.  A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits , 2009, Nature Genetics.

[8]  Ingrid Agartz,et al.  Association study of PDE4B gene variants in scandinavian schizophrenia and bipolar disorder multicenter case–control samples , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[9]  F B Ortega,et al.  Harmonization process and reliability assessment of anthropometric measurements in a multicenter study in adolescents , 2008, International Journal of Obesity.

[10]  Scott F. Saccone,et al.  An autosomal linkage scan for cannabis use disorders in the nicotine addiction genetics project. , 2008, Archives of general psychiatry.

[11]  M. Spurlock,et al.  The development of porcine models of obesity and the metabolic syndrome. , 2008, The Journal of nutrition.

[12]  R. Bates,et al.  Quantitative trait locus mapping in an F2 Duroc x Pietrain resource population: II. Carcass and meat quality traits. , 2008, Journal of animal science.

[13]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[14]  C. Haley,et al.  Genomewide Rapid Association Using Mixed Model and Regression: A Fast and Simple Method For Genomewide Pedigree-Based Quantitative Trait Loci Association Analysis , 2007, Genetics.

[15]  Xavier Estivill,et al.  SNPassoc: an R package to perform whole genome association studies , 2007, Bioinform..

[16]  S. Kahn,et al.  Mechanisms linking obesity to insulin resistance and type 2 diabetes , 2006, Nature.

[17]  M. Setou,et al.  TTLL7 Is a Mammalian β-Tubulin Polyglutamylase Required for Growth of MAP2-positive Neurites* , 2006, Journal of Biological Chemistry.

[18]  G. Plastow,et al.  Association between body composition of growing pigs determined by magnetic resonance imaging, deuterium dilution technique, and chemical analysis. , 2006, Meat science.

[19]  Katherine S. Pollard,et al.  The UCSC Archaeal Genome Browser , 2005, Nucleic Acids Res..

[20]  M. Borodovsky,et al.  Gene identification in novel eukaryotic genomes by self-training algorithm , 2005, Nucleic acids research.

[21]  Jennifer E. Chubb,et al.  DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling , 2005, Science.

[22]  T. Brümmendorf,et al.  Neurotractin/kilon promotes neurite outgrowth and is expressed on reactive astrocytes after entorhinal cortex lesion , 2005, Molecular and Cellular Neuroscience.

[23]  E. Matisoo-Smith,et al.  Worldwide Phylogeography of Wild Boar Reveals Multiple Centers of Pig Domestication , 2005, Science.

[24]  C. Óvilo,et al.  Fine mapping of porcine chromosome 6 QTL and LEPR effects on body composition in multiple generations of an Iberian by Landrace intercross. , 2005, Genetical research.

[25]  S. Lien,et al.  Fine mapping of a QTL for intramuscular fat on porcine chromosome 6 using combined linkage and linkage disequilibrium mapping. , 2005, Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie.

[26]  Burkhard Morgenstern,et al.  AUGUSTUS: a web server for gene finding in eukaryotes , 2004, Nucleic Acids Res..

[27]  Andreas Rolfs,et al.  The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins , 2004, Pflügers Archiv.

[28]  J. Jeon,et al.  A large-insert porcine library with sevenfold genome coverage: a tool for positional cloning of candidate genes for major quantitative traits. , 2003, Molecules and cells.

[29]  D. Levy,et al.  Obesity and the risk of heart failure. , 2003, The New England journal of medicine.

[30]  S. Lien,et al.  Multivariate mixed inheritance models for QTL detection on porcine chromosome 6. , 2003, Genetical research.

[31]  Miguel Pérez-Enciso,et al.  Test for positional candidate genes for body composition on pig chromosome 6 , 2002, Genetics Selection Evolution.

[32]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[33]  J. Dekkers,et al.  A molecular genome scan analysis to identify chromosomal regions influencing economic traits in the pig. II. Meat and muscle composition , 2001, Mammalian Genome.

[34]  J. Kijas,et al.  A Phylogenetic Study of the Origin of the Domestic Pig Estimated from the Near-Complete mtDNA Genome , 2001, Journal of Molecular Evolution.

[35]  S. Lien,et al.  Detection of quantitative trait loci for meat quality in a commercial slaughter pig cross , 2001, Mammalian Genome.

[36]  T. Lakka,et al.  Abdominal obesity is associated with accelerated progression of carotid atherosclerosis in men. , 2001, Atherosclerosis.

[37]  M. Groenen,et al.  Genome-wide scan for body composition in pigs reveals important role of imprinting. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  C. Óvilo,et al.  A QTL for intramuscular fat and backfat thickness is located on porcine Chromosome 6 , 2000, Mammalian Genome.

[39]  M. Groenen,et al.  The effect of adipocyte and heart fatty acid-binding protein genes on intramuscular fat and backfat content in Meishan crossbred pigs. , 2000, Journal of animal science.

[40]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[41]  Kazuro Furukawa,et al.  Molecular Cloning of Brain-specific GD1α Synthase (ST6GalNAc V) Containing CAG/Glutamine Repeats* , 1999, The Journal of Biological Chemistry.

[42]  Friedrich Buck,et al.  Neurotractin, A Novel Neurite Outgrowth-promoting Ig-like Protein that Interacts with CEPU-1 and LAMP , 1999, The Journal of cell biology.

[43]  F. Gerbens,et al.  Effect of genetic variants of the heart fatty acid-binding protein gene on intramuscular fat and performance traits in pigs. , 1999, Journal of animal science.

[44]  S. Karlin,et al.  Finding the genes in genomic DNA. , 1998, Current opinion in structural biology.

[45]  C. Wollheim,et al.  Ca2+‐independent insulin exocytosis induced by α‐latrotoxin requires latrophilin, a G protein‐coupled receptor , 1998, The EMBO journal.

[46]  N. Shimizu,et al.  Human BAC library: construction and rapid screening. , 1997, Gene.

[47]  J. Durnin,et al.  Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 Years , 1974, British Journal of Nutrition.

[48]  David B Goldstein,et al.  Genome-wide scan of copy number variation in late-onset Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[49]  Christian Gieger,et al.  Six new loci associated with body mass index highlight a neuronal influence on body weight regulation , 2009, Nature Genetics.

[50]  Ellen Kampman,et al.  Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity , 2009, Nature Genetics.

[51]  Daiya Takai,et al.  The CpG Island Searcher: A new WWW resource , 2003, Silico Biol..

[52]  D. Haussler,et al.  Human-mouse alignments with BLASTZ. , 2003, Genome research.

[53]  Y. Choy,et al.  Ear Type and Coat Color on Growth Performances of Crossbred Pigs , 2002 .

[54]  H. K. Lee,et al.  Genetic Analyses of Carcass Characteristics in Crossbred Pigs: Cross between Landrace Sows and Korean Wild Boars , 2002 .

[55]  Robin Thompson,et al.  ASREML user guide release 1.0 , 2002 .

[56]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[57]  C. R. Henderson.  Applications of linear models in animal breeding , 1984 .