title: European lactase persistence genotype shows evidence of association with increase in body mass index.
abstract: 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.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK. johannes@sanger.ac.uk
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Kaisa
authors.initials: K
authors.lastname: Silander
authors.forename: Olli
authors.initials: O
authors.lastname: Saarela
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Nicholas
authors.initials: N
authors.lastname: Timpson
authors.forename: Ida
authors.initials: I
authors.lastname: Surakka
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Hartikainen
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Päivi
authors.initials: P
authors.lastname: Lahermo
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.forename: Satu
authors.initials: S
authors.lastname: Männistö
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Olli
authors.initials: O
authors.lastname: Raitakari
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Erich H
authors.initials: EH
authors.lastname: Wichmann
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Van Duijn
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: 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
chemical_list: D043322:Lactase