Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels

Abstract

Objective: To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association.

Design: Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model.

Setting: Alzheimer's Disease Research Center. Subjects We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals.

Main outcome measures: Age at onset and GRN plasma levels.

Results: The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.

Conclusions: The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.

Figure 1. rs1990622 is associated with age at onset of FTLD-TDP in GRN mutation carriers and with GRN plasma levels in non-demented individuals

A) Age at onset was analyzed for association with rs1990622 in 50 GRN mutation carriers by the Kaplan-Meier method and tested for significant differences, using a proportional hazards model (proc PHREG, SAS). Family and gender were included in the model to take into account the relatedness between samples and the potential differences in age at onset between mutations. Healthy mutation carriers were included in the analyses as censored data. Homozygotes for the major allele have an earlier AAO than the heterozygotes and homozygotes for the minor allele (mean age at onset 58 vs. 74 years; p=9.9×10⁻⁷). B) GRN plasma levels were measured in 79 healthy individuals and tested for association with rs1990622. Rs1990622 showed a significant association with GRN plasma levels (p =4×10⁻⁴). C) TMEM106B frontal cortex mRNA levels measured in 40 healthy individuals by Real-Time PCR showed no association with rs1990622 (p=0.78). TMEM106B RNA*; levels corrected for gender and postmortem interval.