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- Fogh, Isabella, et al.
(författare)
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A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis
- 2014
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Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:8, s. 2220-2231
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Tidskriftsartikel (refereegranskat)abstract
- Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
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| 2. |
- Kenna, Kevin P., et al.
(författare)
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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1037-1042
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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| 4. |
- Trevisan, Caterina, et al.
(författare)
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Judgment Capacity, Fear of Falling, and the Risk of Falls in Community-Dwelling Older Adults : The Progetto Veneto Anziani Longitudinal Study
- 2020
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Ingår i: Rejuvenation Research. - : Mary Ann Liebert Inc. - 1549-1684 .- 1557-8577. ; 23:3, s. 237-244
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Tidskriftsartikel (refereegranskat)abstract
- Little is known of the factors that transform fear of falling (FOF) from a normal adaptive to a maladaptive response that could alter its impact on fall risk. Focusing on judgment capacity, we investigated whether it is associated with FOF and FOF-related activity restriction (AR), and whether it modifies the influence of FOF on fall risk. Data came from 2625 community-dwelling older adults enrolled in the Progetto Veneto Anziani. Baseline FOF and AR were assessed through personal interviews, and judgment capacity-high, moderate, or poor-through situational tests. At follow-up after 4.4 years, self-reported falls during the previous year were recorded. The associations between judgment and FOF/AR, and between FOF and the risk of at least one fall or recurrent falls (two or more falls), stratified by judgment capacity, were evaluated using multinomial logistic regressions. Compared with high-judgment participants, lower judgment participants were 20% more likely to report FOF; moderate judgment participants were 54% more likely and poor judgment participants twice as likely to report AR. After adjusting for potential confounders, including physical activity and physical performance, FOF increased the reporting of at least one fall only in the poor judgment group. The association between FOF and recurrent falls was stronger in individuals with poor (odds ratio [OR] = 3.66, 95% confidence interval [CI]: 2.10-6.36) than with moderate (OR = 2.81, 95% CI: 2.22-3.55) or high (OR = 1.65, 95% CI: 1.48-1.83) judgment. Poor judgment capacity increases the probability of FOF and AR in older adults, and may exacerbate the effect of FOF in increasing fall risk.
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