European lactase persistence genotype shows evidence of association with increase in body mass index.
The global prevalence of obesity has increased significantly in recent decades, mainly due to excess calorie intake and increasingly sedentary lifestyle. Here, we test the association between obesity measured by body mass index (BMI) and one of the best-known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments. We genetically defined lactase persistence (LP) in 31 720 individuals from eight European population-based studies and one family study by genotyping or imputing the European LP variant (rs4988235). We performed a meta-analysis by pooling the beta-coefficient estimates of the relationship between rs4988235 and BMI from the nine studies and found that the carriers of the allele responsible for LP among Europeans showed higher BMI (P = 7.9 x 10(-5)). Since this locus has been shown to be prone to population stratification, we paid special attention to reveal any population substructure which might be responsible for the association signal. The best evidence of exclusion of stratification came from the Dutch family sample which is robust for stratification. In this study, we highlight issues in model selection in the genome-wide association studies and problems in imputation of these special genomic regions.
Kettunen
Johannes
J
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK. johannes@sanger.ac.uk
Silander
Kaisa
K
Saarela
Olli
O
Amin
Najaf
N
Müller
Martina
M
Timpson
Nicholas
N
Surakka
Ida
I
Ripatti
Samuli
S
Laitinen
Jaana
J
Hartikainen
Anna-Liisa
AL
Pouta
Anneli
A
Lahermo
Päivi
P
Anttila
Verneri
V
Männistö
Satu
S
Jula
Antti
A
Virtamo
Jarmo
J
Salomaa
Veikko
V
Lehtimäki
Terho
T
Raitakari
Olli
O
Gieger
Christian
C
Wichmann
Erich H
EH
Van Duijn
Cornelia M
CM
Smith
George Davey
GD
McCarthy
Mark I
MI
Järvelin
Marjo-Riitta
MR
Perola
Markus
M
Peltonen
Leena
L
D000328:Adult; D000368:Aged; D015992:Body Mass Index; D015331:Cohort Studies; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D043322:Lactase / Q000235:genetics*; D016014:Linear Models; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D018401:Sample Size; D012727:Sex Characteristics
D043322:Lactase