ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation
ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation
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DOI：
10.1016/j.schres.2010.12.009
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发表时间：
2011-04-01
影响因子：
4.5
通讯作者：
Barnes, Michael R.
中科院分区：
文献类型：
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作者：
Dow, David J.;Huxley-Jones, Julie;Barnes, Michael R.
我们之前报道了与ADAMTSL3基因推测的功能变异的关联，在精神分裂症的全基因组关联研究中仅低于全基因组意义。由于影响ADAMTSL3功能的变异（一种具有血小板反应蛋白I型基序的崩解素样和金属蛋白酶结构域-样-3）可能阐明一种新的疾病机制和潜在的特异性靶点，我们使用互补方法进一步评估这种关联。我们利用来自HapMap和1000基因组计划的数据进行了基因型输入和高密度关联分析。为了回顾所有可能导致这种关联的变异，并确定其他可能的致病性罕见变异，我们对92名精神分裂症患者的ADAMTSL3进行了测序。通过测序共鉴定出71个ADAMTSL3变异，其中许多也在1000个基因组数据中发现，但26个是新发现的。重测序鉴定的变异与相关标记均不存在强连锁不平衡（LD）。归算分析细化了ADAMTSL3与精神分裂症之间的关联，并强调了具有相似关联水平的其他常见变异。我们评估了通过测序确定的所有变异的功能后果，或显示直接或估算的关联。功能的最有力证据仍然是最初相关的变异rs950169，这表明该变异可能是关联的原因。罕见的变异也被确定为可能的功能影响。我们的研究证实了ADAMTSL3是进一步研究精神分裂症的候选基因，使用这里发现的变异。该研究证明了归因分析的效用，我们建议更广泛地使用这种方法来重新评估现有的暗示性精神分裂症相关标准。(C) 2011 Elsevier B.V.版权所有
We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re-sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations. (C) 2011 Elsevier B.V. All rights reserved.