First identification of role TMEM106B in FTD

Van Deerlin et al., Nat Genet. 2010

• GWAS in FTLD-TDP

patients with and without

mutations in GRN showed

genome-wide significant

association with 3 SNPs in

TMEM106B (Top SNP =

rs1990622)

• Unexpectedly, effect was

most pronounced in GRN

mutation carriers.

GRN +

GRN -

Confirmation of TMEM106B association in GRNmutation carriers

2

Finch et al., 2011

• All studies have consistently shown that frequency of homozygous minor allele carriers of TMEM106B SNPs is 15-20% in controls and 1-2% in GRN mutation carriers.

• This suggests that individuals with a GRN mutation need at least one TMEM106B risk allele to develop symptoms; OR GRN mutation carriers without any TMEM106B risk alleles are highly protected from developing FTD and may not be seen in a dementia clinic.

• TMEM106B risk allele was associated with a decrease in age at disease onset in 4 large GRN families.

TMEM106B

Unpublished

• Only one coding variant (p.T185S) on the associated haplotype; also many non-coding variants

TMEM106B variants might regulate TMEM106B expression

TMEM106B mRNA? TMEM106B protein?

Protective TMEM106B variant associated with lower TMEM106B expression?

Does TMEM106B variant affect GRN levels?

• Early studies reported that TMEM106B risk allele was associated with lower GRN levels in plasma (Finch et al. 2011, Cruchaga et al. 2011) but effects are small!

• In CSF samples of

healthy controls, we do

not detect effect of

TMEM106B genotypes

on GRN levels by ELISA

(n=140) (unpublished)

TMEM106B in non-GRN TDP-43 proteinopathies

5

19.1 7.2 8.5 16.7

Van Blitterswijk et al., 2014

Gallagher et al., 2014

• TMEM106B minor alleles protect against FTD in C9ORF72 carriers (though not as pronounced as observed in GRN carriers)

• TMEM106B minor alleles protect against TDP-43 pathology in range of

other diseases including Alzheimer’s disease

• TMEM106B is associated with hippocampal sclerosis of aging pathology

J Neuropathol Exp Neurol,

2015