FTO haplotyping underlines high obesity risk for European populations

Abstract

Background: Fat mass and obesity-associated (FTO) gene has been under close investigation since the discovery of its high impact on the obesity status in 2007 by a range of publications. Recent report on its implication in adipocytes underscored its molecular and functional mechanics in pathology. Still, the population specific features of the locus structure have not been approached in detail.

Methods: We analyzed the population specific haplotype profiles of FTO genomic locus identified by Genome Wide Association Studies (GWAS) for the high obesity risk by examining eighteen 1000G populations from 4 continental groups. The GWAS SNPs cluster is located in the FTO gene intron 1 spanning around 70 kb.

Results: We reconstructed the ancestral state of the locus, which comprised low-risk major allele found in all populations, and two minor risk-associated alleles, each one specific for African and European populations, correspondingly. The locus structure and its allele frequency distribution underscore the high risk allele frequency specifically for the European population. South Asian populations have the second highest frequency of risk alleles, while East Asian populations have the lowest. African population-specific minor allele was only partially risk-associated. All of the GWAS SNPs considered are manifested by low risk alleles as reference (major) ones (p > 0.5) in each of the continental groups. Strikingly, rs1421085, recently reported as a causal SNP, was found to be monomorphic in ancestral (African) populations, implying possible selection sweep in the course of its rapid fixation, as reported previously.

Conclusion: The observations underscore varying FTO -linked risk in the manifestation of population specific epidemiology of genetically bound obesity. The results imply that the FTO locus is one of the major genetic determinants for obesity risk from GWAS SNPs set.

Keywords: FTO gene; Genomics; Haplotypes; Obesity; Population genetics.

Fig. 1

Target cluster of SNPs within FTO intron 1 across the chromosome and number of GWAS citations (see Additional File 1, Table S1). Bold typed is a casual SNP elucidated in (Claussnitzer et al., 2015)

Fig. 2

SNPs frequencies distributions (major low-risk haplotype total wise; Fig. 4) and four haplotype blocks in AFR population. Positions correspond to SNPs in Table 1

Fig. 3

MDS plot based on Fcon values of 18 populations based across FTO intron 1 15 loci, retrieved from 1000G 4 supergroups (AFR, EAS, SAS, EUR; encircled)

Fig. 4

ML haplotypes evolution phylogenetic tree depicting ancestral state and allele frequencies distribution. Compressed 10-letters haplotypes exclude 2, 5, 7–9 positions according to small variation score between populations (Amova results: Table 2; Fig. 2). Frequencies comprise both first position alleles. The risk-associated alleles are colored by red. SNPs diverged from ancestral state are underlined. Bold type corresponds to first position altered in each of allele. The second position is the highest replicated allele rs1421085 (Table 1) affecting adipocyte metabolism (Claussnitzer et al., 2015)

Fig. 5

PCA analysis of haplotypes distribution. Population wise major low-risk allele is encircled and bold typed. Risk-associated allele is bold italic and features EUR populations. Two ‘intermediate’ alleles are marked with italic

Fig. 6

6 major 15-letter haplotypes in 3 populations (Table 4) ‘Healthiest-1’ phenotype maintains altered first position compared to ‘Healthiest’. ‘Intermediate’ comprises more than 1 risk-associated positions (see Fig. 5)