Department of Neurology, Rudolf Magnus Institute of Neuroscience, Genetics, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
Hum Mol Genet. 2010 Oct 15;19(20):4091-9. doi: 10.1093/hmg/ddq323. Epub 2010 Aug 4.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，选择性地影响大脑和脊髓中的运动神经元。最近的全基因组关联研究（GWAS）已经确定了几个增加疾病易感性的常见变体。相比之下，与几种神经精神特征相关的罕见拷贝数变异（CNVs）尚未在具有足够效力的研究人群中针对 ALS 进行研究。为了研究罕见 CNVs 在 ALS 易感性中的作用，我们进行了一项包含超过 19000 人的 CNV 关联研究。在对 1875 例病例和 8731 例对照的全基因组筛查中，我们没有发现病例和对照之间整体 CNV 负担存在差异的证据。在我们的关联分析中，我们确定了两个符合后续研究标准的位点：DPP6 位点（OR=3.59，P=6.6×10(-3)），该位点已经与 ALS 发病机制有关，以及 15q11.2 位点，其中包含 NIPA1（OR=12.46，P=9.3×10(-5)），该基因导致遗传性痉挛性截瘫 6 型（HSP6）。我们在 2559 例病例和 5887 例对照的复制队列中测试了这些位点。结果再次提示存在关联，但不符合我们独立复制的标准：DPP6 位点：OR=1.92，P=0.097，合并结果：OR=2.64，P=1.4×10(-3)；NIPA1：OR=3.23，P=0.041，合并结果：OR=6.20，P=2.2×10(-5)）。我们的结果突出了 DPP6 和 NIPA1 作为进一步深入研究的候选基因。与其他复杂的神经和精神特征不同，具有高效应大小的罕见 CNVs 并未在 ALS 发病机制中起主要作用。
