Linkage and genome-wide association analysis of obesity-related phenotypes: association of weight with the MGAT1 gene.
As major risk-factors for diabetes and cardiovascular diseases, the genetic contribution to obesity-related traits has been of interest for decades. Recently, a limited number of common genetic variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome-wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome-wide level (nominal P < 1.6 x 10(-7), Bonferroni-adjusted P < 0.05) one single-nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 x 10(-8)) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women.
Department of Genetics and Pathology, Rudbeck laboratory, Uppsala University, Uppsala, Sweden.
Asa
A
Johansson
Fabio
F
Marroni
Caroline
C
Hayward
Christopher S
CS
Franklin
Anatoly V
AV
Kirichenko
Inger
I
Jonasson
Andrew A
AA
Hicks
Veronique
V
Vitart
Aaron
A
Isaacs
Tatiana
T
Axenovich
Susan
S
Campbell
Jamie
J
Floyd
Nick
N
Hastie
Sara
S
Knott
Gordan
G
Lauc
Irene
I
Pichler
Kresimir
K
Rotim
Sarah H
SH
Wild
Irina V
IV
Zorkoltseva
James F
JF
Wilson
Igor
I
Rudan
Harry
H
Campbell
Cristian
C
Pattaro
Peter
P
Pramstaller
Ben A
BA
Oostra
Alan F
AF
Wright
Cornelia M
CM
van Duijn
Yurii S
YS
Aulchenko
Ulf
U
Gyllensten
D000217:Acyltransferases / Q000235:genetics*; D015992:Body Mass Index; D002874:Chromosome Mapping; D004041:Dietary Fats / Q000378:metabolism*; D005060:Europe; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D005810:Multigene Family; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D004041:Dietary Fats; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase