Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia

被引:43
作者
Mishra, Aniket [1 ]
Ferrari, Raffaele [2 ]
Heutink, Peter [3 ,4 ]
Hardy, John [2 ]
Pijnenburg, Yolande [5 ,6 ]
Posthuma, Danielle [1 ,7 ]
机构
[1] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, NL-1081 HV Amsterdam, Netherlands
[2] UCL, Dept Mol Neurosci, Russell Sq House,9-12 Russell Sq House, London WC1B 5EH, England
[3] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany
[4] German Ctr Neurodegenerat Dis DZNE Tubingen, D-72076 Tubingen, Germany
[5] VU Univ Med Ctr VUMC, Alzheimer Ctr, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands
[6] VU Univ Med Ctr VUMC, Dept Neurol, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands
[7] VU Univ Med Ctr VUMC, Dept Clin Genet, Neurosci Campus Amsterdam, NL-1081 HV Amsterdam, Netherlands
关键词
gene-based association study; GWAS; FTD; MAGMA; stress-signalling pathway; CORTICOSTEROID-BINDING GLOBULIN; LOBAR DEGENERATION; ALZHEIMERS-DISEASE; BEHAVIORAL VARIANT; APOLIPOPROTEIN-E; HERITABILITY; ACTIVATION; EPSILON-4; CONSENSUS; CRITERIA;
D O I
10.1093/brain/awx066
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small sample size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the epsilon 2 and epsilon 4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.
引用
收藏
页码:1437 / 1446
页数:10
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