rs1108086 — FTO FTO Intron 8 T>C

FTO Intron 8: A Distinct Variant at the Obesity Gene Locus

The FTO (fat mass and obesity-associated) gene spans more than 400 kilobases on chromosome 16, containing nine exons and multiple functionally distinct intronic regions. The well-known FTO obesity signal resides in intron 1 (rs9939609, rs1421085), but rs1108086 sits in a completely different part of the gene — intron 8¹¹ intron 8
The eighth non-coding interval in the FTO pre-mRNA, approximately 100 kb downstream of the primary obesity cluster at chromosome 16 position 54,066,457 (GRCh38). The two regions are in very low linkage disequilibrium²² very low linkage disequilibrium
r² ≈ 0.11 in CEU populations — knowing your rs1108086 genotype tells you almost nothing about your rs9939609 genotype, making this an essentially independent locus within the same gene.

rs1108086 is in very high LD with rs1420318 (r² = 0.953 in Europeans), meaning both variants tag the same intron-8 haplotype. Carriers of the C allele at rs1108086 almost certainly carry the corresponding A allele at rs1420318, and vice versa — the two variants represent the same underlying functional signal.

The Evidence

Published evidence for this locus comes from two independent research programs. The first involves bone mineral density (BMD)³³ bone mineral density (BMD)
A measure of bone mass used to assess fracture risk and diagnose osteoporosis. A 2011 study by Guo et al. tested 141 FTO SNPs for BMD associations 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 and including the same haplotype block as rs1108086 — 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, the proxy variant rs1420318 showed a nominal association with spine BMD (p = 6.14×10⁻³). These associations are biologically plausible: FTO is an m6A RNA demethylase⁴⁴ m6A RNA demethylase
Removes N6-methyladenosine modifications from mRNA to regulate gene expression expressed in osteoblast-rich tissues, and body weight (modulated by the intron-1 variants) is itself a major determinant of bone loading.

The second line of evidence comes from a 2013 study by Wang et al.⁵⁵ 2013 study by Wang et al.
Genetic variants in the fat mass- and obesity-associated (FTO) gene are associated with alcohol dependence. Journal of Molecular Neuroscience that screened 167 FTO SNPs across two Caucasian samples (COGA: 660 cases/400 controls; SAGE: 623 cases/1,016 controls). rs1108086 ranked among the top three FTO SNPs associated with alcohol dependence in the SAGE cohort (p = 0.00086). This finding resonates with FTO's broader role in appetite and reward circuitry beyond adiposity alone — FTO is highly expressed in hypothalamic neurons and modulates dopaminergic signaling pathways relevant to substance use as well as eating behavior.

Both associations remain emerging⁶⁶ emerging
Neither reached genome-wide significance (p < 5×10⁻⁸), and neither has been independently replicated in multiple large cohorts at this specific locus. The BMD association was stronger in Chinese than in Caucasian populations, and the alcohol signal appeared in one of two studied cohorts.

Practical Implications

The intron-8 locus does not participate in the IRX3/IRX5 thermogenesis mechanism that drives FTO's obesity association. Carriers of the C allele at rs1108086 do not have the beige-to-white adipocyte shift associated with the intron-1 cluster. Instead, the available evidence points toward two distinct areas: bone mineral density monitoring (particularly hip and spine BMD, where the intron-8 signal was detected) and awareness of alcohol susceptibility signals. The C allele is particularly common in African and South Asian ancestry groups (~49% and ~41% respectively), compared to only ~13% in Europeans.

Interactions

rs1108086 and rs1420318 are near-redundant tags for the same intron-8 haplotype (r² = 0.953 in Europeans). They should not both generate independent compound actions — users who match one almost certainly match the other. By contrast, rs1108086 and the intron-1 obesity variants (rs9939609, rs1421085) are in low LD (r² ≈ 0.11) and can be independently inherited, representing additive effects at different functional regions of FTO.