Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.
Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.
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全基因组荟萃分析发现ACSL5-ZDHHC6基因座与ALS相关，并将减肥与疾病遗传学联系起来。
DOI：
10.1016/j.celrep.2020.108323
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发表时间：
2020-10-27
期刊：
影响因子：
8.8
通讯作者：
Al-Chalabi A
中科院分区：
文献类型：
--
作者：
Iacoangeli A;Lin T;Al Khleifat A;Jones AR;Opie-Martin S;Coleman JRI;Shatunov A;Sproviero W;Williams KL;Garton F;Restuadi R;Henders AK;Mather KA;Needham M;Mathers S;Nicholson GA;Rowe DB;Henderson R;McCombe PA;Pamphlett R;Blair IP;Schultz D;Sachdev PS;Newhouse SJ;Proitsi P;Fogh I;Ngo ST;Dobson RJB;Wray NR;Steyn FJ;Al-Chalabi A
我们荟萃分析了欧洲和中国人群（84，694例）的肌萎缩侧索硬化症（ALS）全基因组关联研究（GWAS）数据。我们发现跨越ACSL 5-ZDHHC 6的rs 58854276与ALS（p = 8.3 × 10−9）之间存在额外的显著关联，并在独立的澳大利亚队列（1，502人; p = 0.037）中重复。此外，使用基于基因的分析鉴定了B4 GALNT 1、G2 E3-SCFD 1和TRIP 11-ATXN 3。ACSL 5与快速体重减轻有关，另一个ALS相关基因GPX 3也是如此。体重减轻在ALS患者中很常见，并且与较短的生存期相关。我们研究了ACSL 5和GPX 3单核苷酸多态性（SNP）的影响，使用纵向身体组成和体重数据的77例患者和77名对照。在患者的无脂肪质量中，尽管不显著，但我们观察到了预期方向的影响（rs 58854276：-2.1 ± 1.3 kg/A等位基因，p = 0.053; rs3828599：-1.0 ± 1.3 kg/A等位基因，p = 0.22）。对照组中未观察到任何影响。我们的研究结果支持了对ALS中脂质代谢的日益关注，并将疾病遗传学与患者体重减轻联系起来。ACSL 5-ZDHHC 6关联在独立的澳大利亚队列中复制ACSL 5-ZDHHC 6前导SNP在ACSL 5中，并且是脑组织中ZDHHC 6的eQTL。ACSL 5 SNP可能对ALS患者的无脂肪质量有影响。发现ACSL 5-ZDHHC 6和ALS风险之间的关联，并在澳大利亚队列中复制。他们使用基于基因的分析鉴定了B4 GALNT 1，G2 E3-SCFD 1和TRIP 11-ATXN 3。他们还发现ACSL 5 SNP与患者的低脂肪质量之间存在暗示性关联。
We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10−9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients’ fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: −2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: −1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients. Cross-ethnic meta-analysis finds an association between the ACSL5-ZDHHC6 locus and ALS The ACSL5-ZDHHC6 association is replicated in an independent Australian cohort ACSL5-ZDHHC6 lead SNP is in ACSL5 and is an eQTL of ZDHHC6 in brain tissues ACSL5 SNPs might have an effect on fat-free mass in ALS patients Using meta-analysis of European and Chinese ALS GWAS data, Iacoangeli et al. find an association between ACSL5-ZDHHC6 and ALS risk, with replication in an Australian cohort. They identify B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 using a gene-based analysis. They also find a suggestive association between ACSL5 SNPs and lower fat-free mass in patients.
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