Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Deerlin, Vivianna M. Van; Sleiman, Patrick; Martinez‐Lage, Maria; Chen‐Plotkin, Alice S.; Wang, Li San; Graff‐Radford, Neill R.; Dickson, Dennis W.; Rademakers, Rosa; Boeve, Bradley F.; Grossman, Murray; Arnold, Steven E.; Mann, David; Pickering‐Brown, Stuart; Seelaar, Harro; Heutink, Peter; Swieten, John C. van; Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore; Grafman, Jordan; Hodges, John R.; Spillantini, Maria Grazia; Gilman, Sid; Lieberman, Andrew P.; Kaye, Jeffrey; Woltjer, Randall L.; Bigio, Eileen H.; Mesulam, Marsel; Al‐Sarraj, Safa; Troakes, Claire; Rosenberg, Roger N.; White, Charles L.; Ferrer, Isidro; Lladó, Albert; Neumann, Manuela; Kretzschmar, Hans A.; Hulette, Christine M.; Welsh‐Bohmer, Kathleen A.; Miller, Bruce L.; Alzualde, Ainhoa; Munáin, Adolfo López de; McKee, Ann C.; Gearing, Marla; Levey, Aĺlan I.; Lah, James J.; Hardy, John; Rohrer, Jonathan D.; Lashley, Tammaryn; Mackenzie, Ian R.; Feldman, Howard; Hamilton, Ronald L.; DeKosky, Steven T.; Zee, Julie van der; Kumar‐Singh, Samir; Broeckhoven, Christine Van; Mayeux, Richard; Vonsattel, Jean Paul; Troncoso, Juan C.; Kril, Jillian J.; Kwok, John B.; Halliday, Glenda M.; Bird, Thomas D.; Ince, Paul G.; Shaw, Pamela J.; Cairns, Nigel J.; Morris, John C.; McLean, Catriona; DeCarli, Charles; Ellis, William G.; Freeman, Stefanie H.; Frosch, Matthew P.; Growdon, John H.; Perl, Daniel P.; Sano, Mary; Bennett, David A.; Schneider, Julie A.; Beach, Thomas G.; Reiman, Eric M.; Woodruff, Bryan K.; Cummings, Jeffrey L.; Vinters, Harry V.; Miller, Carol A.; Chui, Helena C.; Alafuzoff, Irina; Hartikainen, Päivi; Seilhean, Danielle; Galasko, Douglas; Masliah, Eliezer; Cotman, Carl W.; Tũón, M. Teresa; Martínez, Maribel; Muñoz, David G.; Carroll, Steven L.; Marson, Daniel C.; Riederer, Peter; Bogdanović, Nenad; Schellenberg, Gerard D.; Hákonarson, Hákon; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1038/ng.536

Cited by 512 publications

(573 citation statements)

References 30 publications

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“…4 Follow-up studies confirmed the importance of TMEM106B in FTLD and suggested that TMEM106B may influence risk for FTLD-TDP by modulating the levels of the secreted growth factor progranulin (GRN). 5 Here, we study the role of TMEM106B in the pathologic presentation of AD using TMEM106B SNP rs1990622, previously associated with reduced levels of GRN in human plasma.…”

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confidence: 87%

TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease

Rutherford

Carrasquillo

et al. 2012

Neurology

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TDP-43 protein is the major component of the ubiquitin-positive inclusions in neurons and glia of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). 1 TDP-43 pathology has also been detected in as many as 56% of patients with Alzheimer disease (AD) and in 70% of patients with AD and concomitant hippocampal sclerosis (HpScl).2 Importantly, clinical, neuropsychological, and imaging studies suggested that the presence of TDP-43 pathology in AD may be associated with a modified phenotype.3 A better understanding of what factors predispose to TDP-43 pathology in AD is therefore critical and could have important clinical implications.Last year, a genome-wide association study identified the uncharacterized transmembrane protein 106B (TMEM106B) as a novel risk factor for FTLD-TDP. 4 Follow-up studies confirmed the importance of TMEM106B in FTLD and suggested that TMEM106B may influence risk for FTLD-TDP by modulating the levels of the secreted growth factor progranulin (GRN). 5 Here, we study the role of TMEM106B in the pathologic presentation of AD using TMEM106B SNP rs1990622, previously associated with reduced levels of GRN in human plasma. 5Methods. We studied a cohort of 907 white AD cases (57% female) from the Mayo Clinic Brain Bank. The neuropathologic diagnosis of AD was made according to NIA-Reagan criteria and mean age at death was 80.3 Ϯ 9.4 years. The presence of HpScl was diagnosed if there were neuronal loss and gliosis in the subiculum and CA1 regions of the hippocampus that were disproportionate to the degree of neurofibrillary degeneration. TDP-43 immunoreactivity was assessed in a standardized section of medial temporal lobe using TDP-43 immunohistochemistry (rabbit polyclonal antibody; ProteinTech Group, Chicago, IL; n ϭ 167) 2 or an affinitypurified C-terminal specific polyclonal antibody to TDP-43 6 (n ϭ 740). Genotyping of TMEM106B rs1990622 was performed using an inventoried Taqman SNP genotyping assay (Applied Biosystems).PLINK software (http://pngu.mgh.harvard.edu/ purcell/plink/) was used to perform logistic regression analysis of TMEM106B rs1990622 under an additive, dominant, and recessive model adjusting for age, sex, and presence of the APOE ⑀4 allele.Results. Out of a total of 907 pathologically confirmed AD cases, 301 cases (33.2%) showed abnormal TDP-43 immunoreactivity. HpScl was present in 88 AD cases (9.7%). Association analyses of TMEM106B rs1990622 in this pathologically confirmed cohort showed a highly significant decrease in the frequency of the rs1990622 C-allele in AD cases with TDP-43 pathology compared to AD cases without TDP-43 pathology (C-allele frequency of 37.8% vs 46.5%; p ϭ 5.0 ϫ 10 Ϫ4 ) ( Ϫ7 in an additive model).The association of rs1990622 with HpScl persisted when all patients with TDP-43 immunoreactivity were excluded from the analyses (OR ϭ 0.42; 95% CI ϭ 0.18 -0.97; p ϭ 0.04 in an additive model) (table e-1 on the Neurology ® Web site at www. neurology.org). Similarly, when all patients with HpScl were excluded fr...

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confidence: 87%

TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease

Rutherford

Carrasquillo

et al. 2012

Neurology

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“…located 6.9 kbp downstream of the gene transmembrane protein 106B (TMEM106B), has been shown to potentially modify both age at onset for GRN-mutation carriers and GRN levels in healthy individuals and GRN-mutation carriers. [30][31][32] Furthermore, inconclusive results on APOE as a modifying factor for FTLD have been reported. 17,18,[33][34][35][36] It has also been speculated that rs5848 in the 3 0 UTR of GRN is a binding site for the micro-RNA miR-659 and may regulate the translation of the GRN mRNA.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

et al. 2013

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“…5,6 Genome-wide association studies in sporadic and familial ALS demonstrated highly significant association with single-nucleotide polymorphisms (SNPs) across a 170-Kb region at 9p21.2. [7][8][9][10][11] A massive GGGGCC hexanucleotide repeat expansion mutation (HREM) has recently been identified within intron 1 of C9ORF72 as the pathogenic mutation responsible for familial and sporadic ALS and FTD in these cases. 12,13 Here we describe HREM mutation frequencies in ALS in five European populations.…”

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confidence: 99%

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

et al. 2012

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A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS þ / ÀFTD from five European cohorts (total n ¼ 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n ¼ 434) and controls (n ¼ 856). Haplotypes were analysed using PLINK and aged using DMLE þ . In a London clinic cohort, the HREM was the most common mutation in familial ALS þ / ÀFTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS þ / ÀFTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, Po10 À8 ). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Cited by 512 publications

References 30 publications

TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease

TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease

Novel progranulin mutations with reduced serum-progranulin levels in frontotemporal lobar degeneration

The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder

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