Table 2. Genes identified in SF GWAS meta-analyses and their relevance to gut motility.
| GWAS locus (tag SNP) | Gene symbol | Gene name | Gene function and potential mechanisms involved |
|---|---|---|---|
| Neurotransmission and synaptic regulation | |||
| rs73142301 | COLQ | Collagen Like Tail Subunit Of Asymmetric Acetylcholinesterase | Anchors acetylcholinesterase at neuromuscular junctions and cholinergic synapses; variants may alter acetylcholine clearance, affecting smooth-muscle contraction and peristalsis. |
| rs11240503* | NFASC† | Neurofascin | Cell adhesion protein involved in axon guidance and formation of nodes of Ranvier; disruption may impair enteric neuronal conduction and coordination of motility patterns. |
| rs4556017* | ACHE‡ | Acetylcholinesterase | Degrades acetylcholine at cholinergic synapses; altered expression or activity may shift excitatory neuromuscular signalling and change motility tone. |
| rs10832353 | CALCB | Calcitonin Related Polypeptide Beta | Encodes β-CGRP, a neuropeptide involved in nociception and sensory motor reflexes; modulation of CGRP signalling may influence gut–brain communication and smooth muscle relaxation. |
| rs12273363* | BDNF | Brain Derived Neurotrophic Factor | Neurotrophin involved in neuronal growth, differentiation, survival and plasticity; alterations of its neurotrophic and neurotransmitter effects in the enteric nervous system may affect motility coordination. |
| rs62073098 | CRHR1 | Corticotropin Releasing Hormone Receptor 1 | Mediates corticotropin-releasing hormone stress responses in the enteric nervous system and smooth muscles; activation enhances motility and visceral hypersensitivity. |
| Bile acids metabolism | |||
| rs71606161 | KLB | KlothoB | Fibroblast growth factor coreceptor, binds to FGF19 contributing to regulation of bile acids synthesis; impaired signalling may disrupt bile-acid composition and thereby alter motility and colonic transit. |
| Epithelial and enterocyte function | |||
| rs11240503* | CDK18† | Cyclin Dependent Kinase 18 | Expressed in BEST4+ enterocytes involved in pH sensing and electrolyte transport; altered activity may contribute to enterocyte and epithelial barrier dysfunction, affecting gut transit. |
| rs4556017* | MUC12‡ | Mucin 12 | Membrane-associated mucin contributing to barrier function, microbial interactions and mucosal hydration; variation may alter mucus thickness and integrity, impacting stool consistency and transit time. |
| rs12700026* | LFNG | Beta-1,3-N-Acetylglucosaminyltransferase Lunatic Fringe | Notch-modifying glycosyltransferase that regulates epithelial differentiation; disruption may shift secretory/absorptive lineage balance and affect motility through altered fluid handling. |
| Vitamin B1 metabolism | |||
| rs12022782* | XPR1 | Xenotropic And Polytropic Retrovirus Receptor 1 | Exporter of inorganic phosphate essential for the conversion of vitamin B1 into TPP; changes may affect production of thiamine derivatives, with downstream effects on cholinergic signalling, affecting gut motility. |
| rs12407945* | SLC35F3 | Solute Carrier Family 35 Member F3 | Transporter regulating thiamine intracellular trafficking and availability; reduced thiamine uptake will decrease TPP conversion, with downstream effects on cholinergic signalling. |
*
Locus fine-mapped at single-variant resolution, corresponding to stronger evidence for a causative role of associated genes/mechanisms.
†
NFASC and CDK18 represent equally good candidates (associated with eQTLs) from the same fine-mapped locus rs11240503.
‡
ACHE and MUC12 represent equally good candidates (associated with eQTLs) from the same fine-mapped locus rs4556017.
CGRP, calcitonin gene-related peptide; eQTL, expression-quantitative trait loci; FGF, fibroblast growth factor; GWAS, genome-wide association study; SF, stool frequency; SNP, single-nucleotide polymorphism; TPP, thiamine pyrophosphate.