Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

Abstract

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 3 10 28 ) near FTO (P 5 3.72 3 10 223 ), TMEM18 (P 5 3.24 3 10 217 ), MC4R (P 5 4.41 3 10 217 ), TNNI3K (P 5 4.32 3 10 211 ), SEC16B (P 5 6.24 3 10 29 ), GNPDA2 (P 5 1.11 3 10 28 ) and POMC (P 5 4.94 3 10 28 ) as well as a potential secondary signal at the POMC locus (rs2118404, P 5 2.4 3 10 25 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18 -90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.

Obesity and FTO: Changing Focus at a Complex Locus

“…Subsequently, genome-wide association studies (GWASs) for obesity-related traits in a myriad of European ancestry populations confirmed that multiple SNPs at the FTO locus were associated with BMI (Graff et al, 2013;Bradfield et al, 2012;Lindgren et al, 2009;Meyre et al, 2009;Scherag et al, 2010;Speliotes et al, 2010;Thorleifsson et al, 2009;Wheeler et al, 2013;Willer et al, 2009). Many other reports found the association of FTO SNPs with BMI in non-European-derived populations, including most populations of Asian ancestry, as well as Hispanic/Latino populations and Pima Indians (reviewed by Loos and Yeo, 2014).…”

“…While SNPs in FTO did not influence birth weight (Horikoshi et al, 2013;Jess et al, 2008;Kilpelä inen et al, 2011a), longitudinal studies revealed that the effect on body weight appeared during early childhood, reaching its peak at young adulthood (Graff et al, 2013;Hardy et al, 2010;Sovio et al, 2011).…”

Genetic variations in SEC16B, MC4R, MAP2K5 and KCTD15 were associated with childhood obesity and interacted with dietary behaviors in Chinese school-age population

“…In our study, to achieve a power of not less than 80%, the SNPs which were reported significantly associated with BMI or WC in GWAS (P ≤ 10 × 10 − 8 ) and minor allele frequencies N 0.10 in Chinese population in the HapMap database, were selected. Nineteen SNPs (rs6548238(TMEM18) (Willer et al, 2009), rs10838738(MTCH2) (Willer et al, 2009), rs10938397(GNPDA2) (Willer et al, 2009), rs11084753(KCTD15) (Willer et al, 2009), rs2815752(NEGR1) (Willer et al, 2009), rs2605100(LYPLAL1) (Lindgren et al, 2009), rs545854(MSRA) (Lindgren et al, 2009), rs987237(TFAP2B) (Lindgren et al, 2009), rs17782313(MC4R) (Meyre et al, 2009), rs2241423(MAP2K5) (Speliotes et al, 2010), rs4929949(RPL27A) (Speliotes et al, 2010), rs6265(BDNF) (Thorleifsson et al, 2009), rs543874(SEC16B) 32, rs7647305(ETV5) (Thorleifsson et al, 2009), rs16933812(PAX5) (Graff et al, 2013), rs9356744(CDKAL1) (Wen et al, 2012), rs2796749(AMD1) (Tabassum et al, 2012), rs9299(HOXB5) (Bradfield et al, 2012) and rs9568856(OLFM4) (Bradfield et al, 2012)) were included in this study (Supplementary Table 1).…”

Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

“…In total, 25 genes with 30 single nucleotide polymorphisms (SNPs) were selected (full list in suppl. Table 1; see www.karger.com/doi/10.1159/000469662 for all supplementary material), most of which have previously been associated with body mass index based on genome-wide association studies [18][19][20][21] . Variation in these genes was used for analysis of the genetic association with 3-and 12-month weight loss success in severely obese subjects enrolled in a commercial lifestyle modification program.…”