TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort

Abstract

In a genome-wide association study of frontotemporal lobar degeneration with pathological inclusions of TAR DNA-binding protein, significant association was obtained with three single nucleotide polymorphisms at 7p21.3, in a region encompassing the gene TMEM106B. This study also suggested a potential modifying effect of TMEM106B on disease since the association was strongest in progranulin mutation carriers. Further, the risk effect seemed to correlate with increased TMEM106B expression in patients. In the present study, we sought to replicate these three findings using an independent Flanders-Belgian cohort of primarily clinically diagnosed patients with frontotemporal lobar degeneration (n = 288). We were able to confirm the association with TMEM106B with a P-value of 0.008 for rs1990622, the top marker from the genome-wide association study [odds ratio 0.75 (95% confidence interval 0.61-0.93)]. Further, high-density single nucleotide polymorphism mapping suggested that the association was solely driven by the gene TMEM106B. Homozygous carriers of the TMEM106B protective alleles had a 50% reduced risk of developing frontotemporal lobar degeneration. However, we were unable to detect a modifying effect of the TMEM106B single nucleotide polymorphisms on onset age in progranulin mutation carriers belonging to an extended, clinical and pathological well-documented founder family segregating a progranulin null mutation. Also, we could not observe significant differences in messenger RNA expression between patients and control individuals in lymphoblast cell lines and in brain frontal cortex. In conclusion, we replicated the genetic TMEM106B association in a primarily clinically diagnosed cohort of patients with frontotemporal lobar degeneration from Flanders-Belgium. Additional studies are needed to unravel the molecular role of TMEM106B in disease onset and pathogenesis.

Figure 1

Linkage disequilibrium pattern at the TMEM106B locus. Linkage disequilibrium plot for Hapmap2 CEU data, D′/LOD colour scheme, interval 12.200–12.270 kb. The linkage disequilibrium structure delineates a 36 kb block including only the TMEM106B gene. The relative position of the three replicated SNPs from the genome-wide association study are indicated by ‘X’.

Figure 2

TMEM106B messenger RNA levels in lymphoblast cell lines and brain frontal cortex by disease status and genotype. TMEM106B messenger RNA expression was measured by quantitative reverse-transcription polymerase chain reaction. (A) Relative gene expression in lymphoblast cell lines from patients (n = 22) compared with control individuals (n = 26). (B) Relative gene expression in lymphoblast cell lines from patients and control individuals pooled according to genotype at rs1990622. (C) Relative gene expression in brain frontal cortex from FTLD-TDP patients (n = 11) compared with control individuals (n = 12). (D) Relative gene expression in brain frontal cortex from patients and control individuals pooled according to genotype at rs1990622. In general, we found no evidence that TMEM106B messenger RNA expression is increased in FTLD patients or that TMEM106B rs1990622 genotype is correlated with gene expression. Circles = patients; squares = controls; horizontal lines = group mean.