A missense variant in SLC39A8 is associated with severe idiopathic scoliosis.

A missense variant in SLC39A8 is associated with severe idiopathic scoliosis.
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DOI:
10.1038/s41467-018-06705-0
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发表时间:
2018-10-09
影响因子:
16.6
通讯作者:
Gurnett CA
Gurnett CA
中科院分区:
综合性期刊1区
文献类型:
--
作者:
Haller G;McCall K;Jenkitkasemwong S;Sadler B;Antunes L;Nikolov M;Whittle J;Upshaw Z;Shin J;Baschal E;Cruchaga C;Harms M;Raggio C;Morcuende JA;Giampietro P;Miller NH;Wise C;Gray RS;Solnica-Krezel L;Knutson M;Dobbs MB;Gurnett CA

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预测严重青少年特发性脊柱侧凸(AIS)的遗传因素在很大程度上是未知的。为了确定与严重AIS相关的遗传变异,我们对457例严重AIS病例和987例对照进行了全外显子组关联研究。我们发现SLC 39 A8(p.Ala391Thr,rs 13107325)的错义SNP与严重AIS相关(P = 1.60 × 10−7,OR = 2.01,CI = 1.54-2.62)。这种多效性SNP先前与BMI、血压、胆固醇和血锰水平相关。我们在第二个队列(841例病例和1095例对照)中复制了这种关联,得出组合P = 7.02 × 10−14,OR = 1.94,CI = 1.63-2.34。临床上,在我们的AIS队列中,rs 13107325的次要等位基因与脊柱弯曲度增大、身高降低、BMI增加和血浆锰降低相关。功能研究表明,减少锰流入介导的SLC 39 A8 p.Ala391Thr变异体和脊椎异常,受损的增长,并减少运动活动slc 39 a8突变斑马鱼。我们的研究结果表明,脊柱侧弯可能是服从饮食干预的可能性。大多数脊柱侧凸被认为是特发性的,在青春期发病(AIS),并有遗传贡献。在这里,作者对来自457例严重AIS病例和987例对照的数据进行了外显子组广泛关联研究,发现SLC 39 A8中的错义变异与AIS相关。
Genetic factors predictive of severe adolescent idiopathic scoliosis (AIS) are largely unknown. To identify genetic variation associated with severe AIS, we performed an exome-wide association study of 457 severe AIS cases and 987 controls. We find a missense SNP in SLC39A8 (p.Ala391Thr, rs13107325) associated with severe AIS (P = 1.60 × 10−7, OR = 2.01, CI = 1.54–2.62). This pleiotropic SNP was previously associated with BMI, blood pressure, cholesterol, and blood manganese level. We replicate the association in a second cohort (841 cases and 1095 controls) resulting in a combined P = 7.02 × 10−14, OR = 1.94, CI = 1.63–2.34. Clinically, the minor allele of rs13107325 is associated with greater spinal curvature, decreased height, increased BMI and lower plasma manganese in our AIS cohort. Functional studies demonstrate reduced manganese influx mediated by the SLC39A8 p.Ala391Thr variant and vertebral abnormalities, impaired growth, and decreased motor activity in slc39a8 mutant zebrafish. Our results suggest the possibility that scoliosis may be amenable to dietary intervention. The majority of scoliosis is considered idiopathic with onset in adolescence (AIS) and has a genetic contribution. Here, the authors perform an exome wide association study of data from 457 severe AIS cases and 987 controls, and find a missense variant in SLC39A8 is associated with AIS.
DOI: 10.1038/nature10405
发表时间: 2011-09-11
期刊: NATURE
影响因子: 64.8
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发表时间: 2015-12-01
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发表时间: 2012-01-15
影响因子: 10.6
作者:
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