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UPenn-Led Team IDs Variants Tied To Dementia Risk

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A University of Pennsylvania-led research team reported online in Nature Genetics yesterday that they have tracked down a region on chromosome 7 that's linked to one of the most common types of dementia.

By performing a genome-wide association study involving post-mortem tissue samples from more than 500 individuals with so-called frontotemporal lobar degeneration (FTLD), the researchers pinpointed several SNPs in a linkage disequilibrium block in a chromosome 7 region called 7p21. Through a series of validation and follow-up experiments, they found these risk SNPs fall in and around a gene called TMEM106B, affecting its expression in brain and other tissues.

"Our data suggest a potential disease mechanism in which risk-associated polymorphisms at 7p21 increase TMEM106B expression and elevated TMEM106B expression increases risk for" FTLD with TAR DNA-binding protein inclusions, senior author Virginia Lee, a pathology and laboratory medicine researcher at the University of Pennsylvania, and her co-authors wrote.

FTLD is a largely inherited type of dementia involving progressive language, behavioral, and personality changes. Past studies have implicated mutations in a chromosome 17 gene called GRN in FTLD, though not all cases involve GRN mutations. And, researchers noted, FTLD symptoms can vary dramatically, even in individuals carrying the same GRN mutations.

In an effort to get to the bottom of this puzzle and find additional genetic risk factors for FTLD, the researchers genotyped 515 post-mortem samples from individuals with FTLD-TDP — a type of FTLD involving TAR DNA-binding protein inclusions — using the Illumina HH550 and 610-Quad BeadChip arrays, as well as 2,509 unaffected controls.

The search turned up a dozen FTLD-TDP-associated SNPs in a linkage disequilibrium block in and around the chromosome 7 gene TMEM106B. Three of these reached genome-wide significance.

The team then verified the association between the chromosome 7 region 7p21 and FTLD-TDP by genotyping another 89 FTLD-TDP cases and 553 controls. The association with 7p21 held up both in cases that had GRN mutations and those that didn't, though the team detected potential associations with additional loci in the cases lacking GRN mutations.

In contrast, though, the association did not hold up when they tested 192 individuals living with FTLD — a finding that the researchers attribute to heterogeneity in FTLD cases.

When they trolled public gene expression databases, the researchers found that at least one of the FTLD-TDP-associated SNPs had been shown to affect the expression of TMEM106B in lymphoblastoid cell lines.

The researchers found a similar affect on the gene's expression when they used quantitative RT-PCR to look at gene expression in 18 of the post-mortem brain samples taken from individuals with FTLD-TDP.

Their results also revealed that individuals with FTLD-TDP had TMEM106B expression in their brain tissue that was more than 2.5 times higher than that found in samples from healthy controls.

"Corroborating our results from the cell lines, expression of TMEM106B was significantly correlated with TMEM106B genotype," the researchers wrote, "with risk-allele carriers showing higher gene expression."

Though they emphasized that more work is needed to characterize TMEM106B variants and their consequences in more individuals with FTLD-TDP, those involved say the GWAS points to a role for the gene and its expression in disease risk, both in the presence and absence of other mutations.

"A better understanding of this gene may in turn provide an opportunity for clinical intervention in an otherwise fatal and devastating neurodegenerative disease," they concluded.

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