Genetic dissection of stool frequency implicates vitamin B1 metabolism and other actionable pathways in the modulation of gut motility.

To identify genes and mechanisms involved in gut motility, providing a foundation for clinical translation.

为了识别涉及肠道运动的基因和机制，为临床转化提供基础。

Methods

We performed a multiancestry genome-wide association study (GWAS) meta-analysisof SF in 268 606 European and East Asian individuals.

我们对268,606名欧洲和东亚个体进行了血清铁(SF)的多祖先全基因组关联研究(GWAS)荟萃分析。

Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships.

估计了遗传性和与其他性状的遗传相关性，并使用孟德尔随机化来测试因果关系。

GWAS signals were fine-mapped and functionally annotated to prioritise candidate genes and pathways.

全基因组关联研究（GWAS）信号已被精细定位并进行功能注释，以优先考虑候选基因和通路。

Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank (UKB).

涉及硫胺素代谢的发现通过在英国生物银行（UKB）进行饮食相互作用分析进行了后续研究。

Results

SF heritability was comparable in Europeans (7.0%) and East Asians (5.6%).

SF 遗传力在欧洲人 (7.0%) 和东亚人 (5.6%) 中相当。

We observed strong genetic correlations with gastrointestinal and psychiatric disorders (rg=0.18-0.47), and causal effects on IBS.

我们观察到与胃肠道和精神障碍的强遗传相关性 (rg=0.18-0.47)，以及对肠易激综合症的因果效应。

Novel correlations with cardiovascular traits (rg=0.12-0.14) were supported by drug signature enrichment analyses.

通过药物特征富集分析支持了与心血管特征的新相关性（rg=0.12-0.14）。

We identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ).

我们确定了21个独立的位点，包括10个新信号，这些信号涉及胆汁酸合成（KLB）和胆碱能信号传导（COLQ）。

Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3 (a thiamine transporter) and XPR1 (phosphate exporter essential for thiamine activation).

精细定位揭示了维生素B1代谢通路，强调了SLC35F3（一种硫胺素转运蛋白）和XPR1（对硫胺素激活至关重要的磷酸盐输出蛋白）的单变异因果效应。

In 98 449 UKB participants, thiamine intake was positively associated with SF (p<0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p<0.0001).

在98,449名UKB参与者中，硫胺素摄入量与SF（血清铁蛋白）呈正相关（p<0.0001），而SLC35F3/XPR1基因型评分显著调节了这种效应（p<0.0001）。

Conclusions

We identify therapeutically tractable mechanisms involved in the control of gut motility, including a previously unrecognised role for vitamin B1.

我们确定了控制肠道运动性的可治疗机制，包括之前未认识到的维生素B1的作用。

These findings warrant mechanistic and clinical studies to evaluate their translational potential in IBS and other dysmotility syndromes.

这些发现需要进行机制和临床研究，以评估它们在肠易激综合症和其他运动障碍综合征中的应用潜力。