Laboratory of Human Genetics of Neurological Disorders, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Avogadro University, 28100, Novara, Italy.
J Neurol. 2022 Aug;269(8):4510-4522. doi: 10.1007/s00415-022-11109-8. Epub 2022 May 12.
Over 200 genetic loci have been associated with multiple sclerosis (MS) explaining ~ 50% of its heritability, suggesting that additional mechanisms may account for the "missing heritability" phenomenon.
To analyze a large cohort of Italian individuals to identify markers associated with MS with potential functional impact in the disease.
We studied 2571 MS and 3234 healthy controls (HC) of continental Italian origin. Discovery phase included a genome wide association study (1727 MS, 2258 HC), with SNPs selected according to their association in the Italian cohort only or in a meta-analysis of signals with a cohort of European ancestry (4088 MS, 7144 HC). Top associated loci were then tested in two Italian cohorts through array-based genotyping (903 MS, 884 HC) and pool-based target sequencing (588 MS, 408 HC). Finally, functional prioritization through conditional eQTL and mQTL has been performed.
Top associated signals overlap with already known MS loci on chromosomes 3 and 17. Three SNPs (rs4267364, rs8070463, rs67919208), all involved in the regulation of TBKBP1, were prioritized to be functionally relevant.
No evidence of novel signal of association with MS specific for the Italian continental population has been found; nevertheless, two MS loci seems to play a relevant role, raising the interest to further investigations for TBKBP1 gene.
已有 200 多个遗传位点与多发性硬化症（MS）相关，解释了其遗传率的~50%，这表明可能存在其他机制来解释“遗传缺失”现象。
分析一个大型的意大利个体队列，以鉴定与 MS 相关的标志物，这些标志物在疾病中可能具有潜在的功能影响。
我们研究了 2571 名 MS 患者和 3234 名意大利裔的健康对照者（HC）。发现阶段包括全基因组关联研究（1727 名 MS 患者，2258 名 HC），根据仅在意大利队列中关联的 SNP 或在具有欧洲血统队列的信号荟萃分析中选择 SNP（4088 名 MS 患者，7144 名 HC）。然后，通过基于阵列的基因分型（903 名 MS 患者，884 名 HC）和基于池的靶向测序（588 名 MS 患者，408 名 HC）在两个意大利队列中测试了最相关的基因座。最后，通过条件性 eQTL 和 mQTL 进行了功能优先级排序。
最相关的信号与染色体 3 和 17 上已有的 MS 位点重叠。三个 SNP（rs4267364、rs8070463、rs67919208）均参与 TBKBP1 的调控，被优先认为具有功能相关性。
未发现与意大利大陆人群特定的 MS 相关的新信号；然而，两个 MS 基因座似乎发挥了重要作用，引起了对 TBKBP1 基因的进一步研究兴趣。
