rs1421085

This neuroimaging study examined differences in brain structure and function in 93 children (ages 5-10) without obesity, stratified by FTO rs1421085 genotype. Homozygous C allele carriers (CC, n=15) showed significantly greater grey matter volume in the cerebellum and temporal fusiform gyrus (p=0.017-0.050), increased bilateral cerebellar white matter fibre density and cross-section (peak t=6.34, p FWE=0.037), and increased resting-state functional connectivity between the cerebellum and frontotemporal cortices compared to homozygous T allele carriers (TT, n=47). This is the first study to examine FTO-related brain differences in young children before obesity onset, suggesting the cerebellum may be a key structure in FTO-mediated obesity risk mechanisms.

A literature review of 70 studies examining single nucleotide polymorphisms (SNPs) associated with obesity in Mexican populations published 2011-2021. The authors identified SNPs with differential behavior in Mexican compared to Caucasian populations, including rs17782313 (MC4R), rs6548238 (TMEM18), rs6265 (BDNF), rs7498665 (SH2B1), and notably rs6232 (PCSK1) associated with early-onset obesity in Mexican youth. The review emphasizes ethnicity-dependent genetic effects on BMI heritability (40-70%) and highlights genes involved in cholesterol metabolism and adipokine signaling pathways.

In a population-based cohort of 3,179 children, the study tested two weighted genetic risk scores based on 15 childhood and 97 adult BMI-associated SNPs, plus ten individual appetite/satiety SNPs, for association with eating behavior measures. The 97 SNP adult BMI risk score was nominally associated with lower satiety responsiveness (β: -0.007 SD, 95% CI -0.013, 0.000), while individual SNPs rs11030104 (BDNF) and rs10733682 (LMX1B) showed nominal associations with reduced satiety responsiveness (β: -0.057 to -0.087 SD). Overall, findings do not strongly support that BMI-associated SNPs influence eating behavior at this young age.

This scoping review examined 18 observational studies (n=26,684) from low- and middle-income countries investigating gene-environment interactions affecting obesity risk. The review found statistically significant associations for 12 individual SNPs including FTO rs1421085, rs9939609, rs10163409, rs3751812, MC4R rs17782313, rs12970134, TMEM18 rs7561317, NEGR1 rs2815752, CARTPT rs2239670, UCP2 rs659366, CLOCK rs1801260, and FLJ33544 rs140133294, though most associations were not replicated across different populations and environmental exposures.

This study examined whether 32 obesity-associated genetic risk alleles are associated with childhood ADHD in a German GWAS sample (495 cases, 1,300 controls) and a meta-analysis (2,064 trios, 896 cases, 2,455 controls). The obesity risk allele G at rs206936 in NUDT3 was associated with increased ADHD risk (OR=1.39, P=3.4×10⁻⁴), and rs6497416 in GPRC5B showed association with ADHD in the meta-analysis (P=7.2×10⁻⁴). Several obesity-related SNPs were associated with ADHD endophenotypes including inattention and hyperactivity/impulsivity.

Genome-wide association study examining common variants near BDNF (rs6265, rs925946) and SH2B1 (rs7498665) in relation to snacking behavior across three European cohorts (French obese children, Swiss obese, D.E.S.I.R.). The study reports nominal evidence of association, with rs925946 in BDNF showing OR=1.21 (p=5.03×10⁻³) in the D.E.S.I.R. cohort and rs7498665 in SH2B1 showing OR=1.17 (p=9.57×10⁻³) in the Swiss cohort.

This case-control study of 2,033 colorectal cancer cases and 9,640 controls investigated whether BMI and waist size susceptibility variants are associated with colorectal cancer risk. Two obesity SNPs showed significant associations: KCTD15 rs29941 (OR = 0.90, p = 0.01) was protective, while MC4R rs17782313 (OR = 1.12, p = 0.02) increased risk. However, neither association remained significant after multiple comparisons correction, and overall obesity variants showed minimal effects on colorectal cancer.

This meta-analysis of eight PCOS cohorts (2,548 women) found that FTO rs9939609 and rs1421085 polymorphisms have significantly greater effects on BMI and body weight in PCOS patients than in the general population. Each additional effect allele increased BMI by 0.19 z-score units (p=2.26×10⁻¹¹) and body weight by 0.20 z-score units (p=1.02×10⁻¹⁰), demonstrating effects more than two times greater than previously reported.

Analysis of 27 FTO gene variants in 1,424 Hispanic Americans and 604 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS) found multiple SNPs associated with BMI, waist circumference, and subcutaneous adipose tissue (p-values 0.001-0.05 in Hispanics), confirming FTO's role in overall fat mass rather than visceral fat distribution. Key variants rs9939609, rs8050136, rs1121980, rs1421085, rs17817449, and rs3751812 showed consistent associations with adiposity measures, with effect sizes of 0.3-2.4 kg/m² per allele for BMI in Hispanic Americans.

This prospective study examined the combined effects of FTO rs1421085 and MC4R rs17782313 obesity risk alleles in two large European cohorts (4,762 Finnish adolescents and 3,167 French adults). Subjects carrying 3-4 risk alleles had a 3-fold increased obesity susceptibility in childhood and 1.8-fold increased risk in adults (OR=1.21, p=0.02), with each additional risk allele increasing fat mass by 0.48% (p=0.001). The effects on type 2 diabetes were mediated through BMI. MC4R showed stronger male-specific effects and FTO effects were accentuated by low physical activity.

In 55 Europid participants, FTO mRNA expression in adipose tissue was 3-fold higher in subcutaneous versus visceral depots and showed significant negative correlations with BMI and body fat percentage. However, the obesity-associated SNP rs8050136 (in linkage disequilibrium with rs9939609) was not associated with FTO or RPGRIP1L mRNA expression levels in either adipose tissue depot.