#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium


Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.


Vyšlo v časopise: Is a Novel Locus for Waist Circumference: A Genome-Wide Association Study from the CHARGE Consortium. PLoS Genet 5(6): e32767. doi:10.1371/journal.pgen.1000539
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000539

Souhrn

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.


Zdroje

1. CassanoPA

RosnerB

VokonasPS

WeissST

1992 Obesity and body fat distribution in relation to the incidence of non-insulin-dependent diabetes mellitus. A prospective cohort study of men in the normative aging study. Am J Epidemiol 136 1474 1486

2. FolsomAR

KushiLH

AndersonKE

MinkPJ

OlsonJE

2000 Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa Women's Health Study. Arch Intern Med 160 2117 2128

3. OhlsonLO

LarssonB

SvardsuddK

WelinL

ErikssonH

1985 The influence of body fat distribution on the incidence of diabetes mellitus. 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 34 1055 1058

4. WeiM

GaskillSP

HaffnerSM

SternMP

1997 Waist circumference as the best predictor of noninsulin dependent diabetes mellitus (NIDDM) compared to body mass index, waist/hip ratio and other anthropometric measurements in Mexican Americans–a 7-year prospective study. Obes Res 5 16 23

5. RankinenT

ZuberiA

ChagnonYC

WeisnagelSJ

ArgyropoulosG

2006 The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14 529 644

6. LyonHN

HirschhornJN

2005 Genetics of common forms of obesity: a brief overview. Am J Clin Nutr 82 215S 217S

7. ChambersJC

ElliottP

ZabanehD

ZhangW

LiY

2008 Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 40 716 718

8. FraylingTM

TimpsonNJ

WeedonMN

ZegginiE

FreathyRM

2007 A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316 889 894

9. LoosRJ

LindgrenCM

LiS

WheelerE

ZhaoJH

2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40 768 775

10. KringSI

HolstC

ZimmermannE

JessT

BerentzenT

2008 FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness. PLoS ONE 3 e2958 doi:10.1371/journal.pone.0002958

11. ThorleifssonG

WaltersGB

GudbjartssonDF

SteinthorsdottirV

SulemP

2008 Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41 18 24

12. WillerCJ

SpeliotesEK

LoosRJ

LiS

LindgrenCM

2009 Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41 25 34

13. MeyreD

DelplanqueJ

ChevreJC

LecoeurC

LobbensS

2009 Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet 41 157 159

14. ServinB

StephensM

2007 Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet 3 e114 doi:10.1371/journal.pgen.0030114

15. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

16. O'ConnellJR

2008 Optimizing Measured Genotype Genome-wide Association Analysis for Quantitative Traits in Pedigrees (Abstract program number 2409). ASHG Annual Meeting. Philadelphia, Pennsylvania

17. TeamRDC

2006 R: A language and environment for statistical computing Vienna, Austria R Foundation for Statistical Computing

18. LiY

DingJ

AbecasisGR

2006 Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference (Abstract program number 2290). ASHG Annual Meeting. New Orleans, Louisiana

19. AulchenkoYS

RipkeS

IsaacsA

van DuijnCM

2007 GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 1294 1296

20. BacanuSA

DevlinB

RoederK

2000 The power of genomic control. Am J Hum Genet 66 1933 1944

21. PriceAL

PattersonNJ

PlengeRM

WeinblattME

ShadickNA

2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909

22. GordonAGG

QuiX

YakovlevA

2007 Control of the mean number of false discoveries, bonferroni and stability of multiple testing. Annals of Applied Statistics 1 179 190

23. LachmanHM

FannCS

BartzisM

EvgrafovOV

RosenthalRN

2007 Genomewide suggestive linkage of opioid dependence to chromosome 14q. Hum Mol Genet 16 1327 1334

24. KelaiS

MaussionG

NobleF

BoniC

RamozN

2008 Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction. Neuroreport 19 751 755

25. ClaySW

AllenJ

ParranT

2008 A review of addiction. Postgrad Med 120 E01 07

26. RapakaR

SchnurP

ShurtleffD

2008 Obesity and addiction: common neurological mechanisms and drug development. Physiol Behav 95 2 9

27. BransonR

PotocznaN

KralJG

LentesKU

HoeheMR

2003 Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 348 1096 1103

28. GerkenT

GirardCA

TungYC

WebbyCJ

SaudekV

2007 The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318 1469 1472

29. CecilJE

TavendaleR

WattP

HetheringtonMM

PalmerCN

2008 An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 359 2558 2566

30. MyersAJ

GibbsJR

WebsterJA

RohrerK

ZhaoA

2007 A survey of genetic human cortical gene expression. Nat Genet 39 1494 1499

31. DixonAL

LiangL

MoffattMF

ChenW

HeathS

2007 A genome-wide association study of global gene expression. Nat Genet 39 1202 1207

32. SchadtEE

MolonyC

ChudinE

HaoK

YangX

2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2009 Číslo 6
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#