European lactase persistence genotype shows evidence of association with increase in body mass index

Johannes Kettunen, Kaisa Silander, Olli Saarela, Najaf Amin, Martina Müller, Nicholas Timpson, Ida Surakka, Samuli Ripatti, Jaana Laitinen, Anna-Liisa Hartikainen, Anneli Pouta, Päivi Lahermo, Verneri Anttila, Satu Männistö, Antti Jula, Jarmo Virtamo, Veikko Salomaa, Terho Lehtimäki, Olli Raitakari, Christian GiegerErich H Wichmann, Cornelia M Van Duijn, George Davey Smith, Mark I McCarthy, Marjo-Riitta Järvelin, Markus Perola, Leena Peltonen

Research output: Contribution to journalArticle (Academic Journal)peer-review

46 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1129-36
Number of pages8
JournalHuman Molecular Genetics
Issue number6
Publication statusPublished - 2010

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