rs5848
| Orientation | minus |
| Stabilized | minus |
| Geno | Mag | Summary |
|---|---|---|
| (A;A) | 3 | Somewhat increased (~2 - 3x) dementia risk |
| (A;G) | 2 | Somewhat increased (~2 - 3x) dementia risk |
| (G;G) | 3 | lower dementia risk |
| Reference | GRCh38 38.1/141 |
| Chromosome | 17 |
| Position | 44352876 |
| Gene | FAM171A2, GRN |
| is a | snp |
| is | mentioned by |
| dbSNP | rs5848 |
| dbSNP (classic) | rs5848 |
| ClinGen | rs5848 |
| ebi | rs5848 |
| HLI | rs5848 |
| Exac | rs5848 |
| Gnomad | rs5848 |
| Varsome | rs5848 |
| LitVar | rs5848 |
| Map | rs5848 |
| PheGenI | rs5848 |
| Biobank | rs5848 |
| 1000 genomes | rs5848 |
| hgdp | rs5848 |
| ensembl | rs5848 |
| geneview | rs5848 |
| scholar | rs5848 |
| rs5848 | |
| pharmgkb | rs5848 |
| gwascentral | rs5848 |
| openSNP | rs5848 |
| 23andMe | rs5848 |
| SNPshot | rs5848 |
| SNPdbe | rs5848 |
| MSV3d | rs5848 |
| GWAS Ctlg | rs5848 |
| GMAF | 0.3861 |
| Max Magnitude | 3 |
| ? | (A;A) (A;G) (G;G) | 28 |
|---|---|---|
|
| ||
rs5848(T;T) found a 3.2-fold increased risk vs C-allele carriers (95% CI: 1.50-6.73, p=0.003) for ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U also knows as FTLD-TDP43), a progressive neurodegenerative disease affecting approximately 10% of early-onset dementia patients. Detailed haplotype analysis was conducted, indicating rs5848 as most likely causal variant. FTLD-TDP43 is divided into four subtypes, some sources suggest association with type 3 only [PMID 16862115]. Association between rs5848(T;T) and frontotemporal dementia is now generally assumed in literature, despite some studies failing to reproduce it.
First meta-analysis of rs5848 association with Alzheimer's disease combining previous five studies for a total of 2502 Alzheimer's disease cases and 2162 controls found association in homozygous model (TT vs. CC: OR, 1.36; 95% CI, 1.11-1.66; P=0.003) as well as recessive model. This association existed also in the Caucasian-only subset of 2227 cases and 1902 controls. Although the p-value is above usually applied guidelines, the researchers concluded the data indicates association exists [PMID 24680777]. According to "First symptoms--frontotemporal dementia versus Alzheimer's disease" [PMID 10940680] as well as other sources frontotemporal dementia is often misdiagnosed as Alzheimer's disease so it is possible some studies have misdiagnosed cases. FTLD is characterized by behavioral and/or language dysfunction, but usually without the amnesic syndrome involved in Alzheimer's disease at early stage.
In contrast "Reduced serum progranulin level might be associated with Parkinson's disease risk" [PMID 23398167] found that only Parkinson's disease was associated with reduces progranulin levels, but found no association between progranulin levels, rs5848 or Alzheimer's disease. "Association between GRN rs5848 polymorphism and Parkinson's disease in Taiwanese population" found association between rs5848 and Parkinson's disease, but only for female Taiwanese (OR = 1.43, 95% CI: 1.11-1.87, P = 0.007 for single T allele among females). Most studies have found association with neurodegenerative disorders only for recessive or homozygous model, but this is one study where odds ratio follows number of alleles (OR=2.16, 95% CI: 1.24-3.78, P = 0.006 for two alleles among females).
A functional effect is suggested in many studies such as "GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer's disease patients" [PMID 22890097] and "Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease" [PMID 19625741
]. In addition "rs5848 polymorphism and serum progranulin level" [PMID 21047645] showed that progranulin level is affected by number of (T) alleles equally both in 100 patients with different forms of dementia and 36 controls: TT (164 ng/mL, 95% C.I. 138-189), CT (191 ng/mL, 95% C.I. 177-206) and CC (222 ng/mL, 95% C.I. 205-238) serum progranulin with p < 0.005. Progranulin is a growth-factor involved in regulating tumorigenesis, wound repair, development, and inflammation among other things. Rs5848 is located in the 3'-untranslated region (UTR) RNA tail of GRN in a binding-site for miR-659 which inhibits GRN translation. University of California, San Francisco is currently conducting clinical trial "Finding Study of Nimodipine for the Treatment of Progranulin Insufficiency From GRN Gene Mutations".
| GWAS snp | |
|---|---|
| PMID | [PMID 24680777] |
| Trait | Alzheimer's disease |
| Title | Progranulin polymorphism rs5848 is associated with increased risk of Alzheimer's disease. |
| Risk Allele | TT |
| P-val | 6E-3 |
| Odds Ratio | 1.31 [1.08-1.58] recessive model |
[PMID 18723524] Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia.
[PMID 19446372] No association of PGRN 3'UTR rs5848 in frontotemporal lobar degeneration
[PMID 19473366] GRN 3'UTR+78 C>T is not associated with risk for Parkinson's disease
[PMID 19847305] Variation at GRN 3'-UTR rs5848 Is Not Associated with a Risk of Frontotemporal Lobar Degeneration in Dutch Population
[PMID 19876635] Sporadic corticobasal syndrome due to FTLD-TDP
[PMID 20197700] Common Variant in GRN Is a Genetic Risk Factor for Hippocampal Sclerosis in the Elderly
[PMID 20061636] GRN variability contributes to sporadic frontotemporal lobar degeneration
[PMID 20711061] Prion Protein Codon 129 Polymorphism Modifies Age at Onset of Frontotemporal Dementia With the C.709-1G>A Progranulin Mutation
[PMID 21047645] rs5848 polymorphism and serum progranulin level
[PMID 21212639] rs5848 Variant of Progranulin Gene Is a Risk of Alzheimer's Disease in the Taiwanese Population
[PMID 16251468] Survey of allelic expression using EST mining.
[PMID 18192287] Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations.
[PMID 19016491] An association study between granulin gene polymorphisms and Alzheimer's disease in Finnish population.
[PMID 19625741] Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease.
[PMID 19640594] Recent insights into the molecular genetics of dementia.
[PMID 21346515] Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically.
[PMID 23342160] Association between GRN rs5848 Polymorphism and Parkinson's Disease in Taiwanese Population
[PMID 24499389] Progranulin gene variability influences the risk for bipolar I disorder, but not bipolar II disorder
[PMID 24581833] Further evidence for plasma progranulin as a biomarker in bipolar disorder
[PMID 22890097] GRN variant rs5848 reduces plasma and brain levels of granulin in Alzheimer's disease patients.
[PMID 23398167] Reduced serum progranulin level might be associated with Parkinson's disease risk.
[PMID 24770881] ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology
| ClinVar | |
|---|---|
| Risk | Rs5848(A;A) |
| Alt | Rs5848(A;A) |
| Reference | Rs5848(G;G) |
| Significance | Other |
| Disease | FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS Frontotemporal dementia |
| Variation | info |
| Gene | GRN |
| CLNDBN | FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS, SUSCEPTIBILITY TO Frontotemporal dementia |
| Reversed | 1 |
| HGVS | NC_000017.10:g.42430244C>T |
| CLNSRC | OMIM Allelic Variant |
| CLNACC | RCV000022594.3, RCV000353944.1, |
[PMID 25470345] Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology
[PMID 28189700] CSF protein changes associated with hippocampal sclerosis risk gene variants highlight impact of GRN/PGRN.
[PMID 29761124] Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment.
