title: Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects.
abstract: Neuropeptide Y (NPY) is an appetite hormone that acts centrally to control feeding behavior. The 5' and exon 2 regions of NPY2R, one of five NPY receptor genes, have been weakly and inconsistently implicated with obesity. With the ATG start site of the gene at the beginning of exon 2, single-nucleotide polymorphisms (SNPs) across intron 1 may show stronger associations with obesity than expected. Two 5' SNPs, three intron 1 SNPs, and one synonymous exon 2 SNP were genotyped on 2,985 white Utah subjects. Previously associated FTO, NPY, NPY1R, MC4R, PPARGC1A, OR7D4, and four NPFFR2 SNPs were also genotyped and related to BMI. One NPY2R 5' SNP (rs12649641, P = 0.008), an exon 2 SNP (rs2880415, P = 0.009), and an intron 1 SNP (rs17376826, P = 7 × 10(-6)) were each significantly associated with BMI. All three SNPs, plus FTO (rs9939609, P = 1.5 × 10(-6)) and two NPFFR2 SNPs (rs4129733, P = 3.7 × 10(-13) and rs11940196, 4.2 × 10(-10)) remained significant in a multiple regression additive model. Diplotypes using the estimated haplotypes of NPY2R, NPFFR2, and MC4R were significantly associated with BMI (P = 1.0 × 10(-10), 3.2 × 10(-8), and 1.1 × 10(-4), respectively). Haplotypes of NPY2R, NPFFR2, and MC4R, plus the FTO SNP, explained 9.6% of the BMI variance. SNP effect sizes per allele for the four genes ranged from 0.8 to 3.5 kg/m(2). We conclude that haplotypes containing the rs17376826 SNP in intron 1 of NPY2R have strong associations with BMI, some NPFFR2 haplotypes are strongly protective against or increase risk of obesity, and both NPY2R and NPFFR2 play important roles in obesity predisposition independent of FTO and MC4R.
authors.affiliation: Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA. steve.hunt@utah.edu
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hasstedt
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Xin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Dalley
authors.forename: Brett A
authors.initials: BA
authors.lastname: Milash
authors.forename: Emanuel
authors.initials: E
authors.lastname: Yakobson
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gress
authors.forename: Lance E
authors.initials: LE
authors.lastname: Davidson
authors.forename: Ted D
authors.initials: TD
authors.lastname: Adams
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D014589:Utah; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D018013:Receptors, Neuropeptide; D017476:Receptors, Neuropeptide Y; C083929:neuropeptide FF receptor; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human