title: Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis.
abstract: TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Vass
authors.forename: Emily
authors.initials: E
authors.lastname: Ashbridge
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.forename: Dana
authors.initials: D
authors.lastname: Clay-Falcone
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics*; D001344:Autopsy; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C556915:TMEM106B protein, human