| 1. |
|
|
| 2. |
|
|
| 3. |
- Bonham, LW, et al.
(författare)
-
Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
-
Tidskriftsartikel (refereegranskat)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Witoelar, A, et al.
(författare)
-
Meta-analysis of Alzheimer's disease on 9,751 samples from Norway and IGAP study identifies four risk loci
- 2018
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 18088-
-
Tidskriftsartikel (refereegranskat)abstract
- A large fraction of genetic risk factors for Alzheimer’s Disease (AD) is still not identified, limiting the understanding of AD pathology and study of therapeutic targets. We conducted a genome-wide association study (GWAS) of AD cases and controls of European descent from the multi-center DemGene network across Norway and two independent European cohorts. In a two-stage process, we first performed a meta-analysis using GWAS results from 2,893 AD cases and 6,858 cognitively normal controls from Norway and 25,580 cases and 48,466 controls from the International Genomics of Alzheimer’s Project (IGAP), denoted the discovery sample. Second, we selected the top hits (p < 1 × 10−6) from the discovery analysis for replication in an Icelandic cohort consisting of 5,341 cases and 110,008 controls. We identified a novel genomic region with genome-wide significant association with AD on chromosome 4 (combined analysis OR = 1.07, p = 2.48 x 10-8). This finding implicated HS3ST1, a gene expressed throughout the brain particularly in the cerebellar cortex. In addition, we identified IGHV1-68 in the discovery sample, previously not associated with AD. We also associated USP6NL/ECHDC3 and BZRAP1-AS1 to AD, confirming findings from a follow-up transethnic study. These new gene loci provide further evidence for AD as a polygenic disorder, and suggest new mechanistic pathways that warrant further investigation.
|
|
