rs1420318 — FTO

FTO Intron 8: A Distinct Variant in the Obesity Gene

The FTO (fat mass and obesity-associated) gene spans chromosome 16 and contains multiple independently associated genetic variants across different introns. While the best-known FTO variants (rs9939609, rs1421085) cluster in intron 1 and drive the well-replicated obesity association, rs1420318 occupies a different region of the gene — intron 8¹¹ intron 8
The eighth non-coding interval within the FTO pre-mRNA, approximately 100 kb downstream of the intron-1 obesity cluster. The two regions are in low linkage disequilibrium²² low linkage disequilibrium
r² ≈ 0.11 in CEU populations, indicating that knowing your rs1420318 genotype tells you very little about your rs9939609 genotype — making rs1420318 an essentially independent locus within the same gene.

rs1420318 is in very high LD with rs1108086 (r² = 0.95 in Europeans), suggesting these two intron-8 variants tag the same underlying haplotype and likely have correlated effects.

The Evidence

Published evidence for rs1420318 comes from two independent lines of research. The first is a 2011 study by Guo et al.³³ Guo et al.
The fat mass and obesity associated gene, FTO, is also associated with osteoporosis phenotypes. PLoS One, 2011 that tested 141 FTO SNPs for associations with bone mineral density (BMD) in two Chinese Han cohorts (N=818 and N=809) and one Caucasian cohort (N=2,286). In Chinese populations, six intron-8 FTO SNPs — all in high mutual LD — showed significant associations with hip BMD (combined p = 1.47×10⁻⁴ to 4.99×10⁻⁴), with each minor allele copy associated with increased hip BMD (β ≈ 0.015–0.025). In the Caucasian sample, rs1420318 specifically showed a nominal association with spine BMD (p = 6.14×10⁻³), though this did not survive multiple-testing correction. The connection between FTO and bone health is biologically plausible: FTO is an RNA demethylase⁴⁴ RNA demethylase
Removes N6-methyladenosine (m6A) modifications from mRNA, influencing translation efficiency of downstream target genes with expression in osteoblast-rich tissues, and body weight itself (which the intron-1 variants influence) is a major determinant of bone loading.

The second line of evidence comes from a 2013 genetic study by Wang et al.⁵⁵ Wang et al.
Genetic variants in the fat mass- and obesity-associated (FTO) gene are associated with alcohol dependence. Journal of Molecular Neuroscience, 2013 that scanned 167 FTO SNPs for associations with alcohol use disorder in two Caucasian populations (COGA: 660 cases/400 controls; SAGE: 623 cases/1,016 controls). rs1420318 ranked among the top three FTO variants associated with alcohol dependence in the SAGE sample (p = 0.00086). No specific odds ratio by genotype was reported. This finding echoes observations that the FTO gene region influences reward and appetite signaling more broadly than just adiposity.

Both associations remain emerging⁶⁶ emerging
Not yet replicated with genome-wide significance or in multiple independent cohorts at the same locus evidence — neither reached genome-wide significance (p < 5×10⁻⁸), and the BMD finding did not replicate across the Chinese and Caucasian samples in the same study.

Practical Implications

Because rs1420318 is not in LD with the rs9939609/rs1421085 intron-1 obesity cluster, it does not capture the established IRX3/IRX5 thermogenesis mechanism. The variant's location in intron 8 puts it in a distinct regulatory context within the FTO gene. For carriers of the A allele — which is particularly common in African populations (~53%) and South Asian populations (~34%), but rare in Europeans (~12%) — the available data suggest two areas worth attention: bone mineral density monitoring (particularly spine BMD, where the nominal Caucasian signal was observed), and mindful engagement with alcohol, given the association signal in the SAGE cohort.

These recommendations reflect current evidence and should be revisited as larger-scale studies provide clearer replication.

Interactions

rs1420318 and rs1108086 (r² = 0.95) are on the same intron-8 haplotype and likely tag the same functional signal. If you carry the A allele at rs1420318, you almost certainly carry the corresponding allele at rs1108086, and vice versa — any compound action combining these two variants would largely be redundant.

The intron-8 haplotype is independent of the intron-1 obesity cluster (rs9939609, rs1421085, rs8050136). Individuals who carry both the intron-1 risk allele and the intron-8 A allele are carrying two independently inherited FTO variants with potentially different biological effects.