Background: Frontotemporal lobar degeneration is a neurodegenerative disease characterized by brain atrophy of the frontal and anterior temporal lobes. The associated frontotemporal dementia syndromes are clinically heterogeneous, and the pattern of affected cortical regions varies among subtypes. The TMEM106B rs1990622 polymorphism is associated with frontotemporal lobar degeneration, but little is known about how it affects the brain. Methods: We investigated the rs1990622 polymorphism in relation to regional brain volumes to identify potential structures through which TMEM106B confers risk for frontotemporal lobar degeneration. In 4413 nondemented and stroke-free participants from the population-based Rotterdam Study, 150 cortical brain structures and 6 commissural regions were segmented from magnetic resonance imaging. Results: A distinct pattern of association was found between rs1990622 and gray matter volume of left-sided temporal brain regions important for language processing, including the superior temporal gyrus (beta = -88.8 mu L per risk allele, p = 7.64 x 10(-5)), which contains Wernicke's area. The risk allele was also associated with a smaller anterior commissure cross-sectional area (beta = -.167 mm(2) per risk allele, p = 4.90 x 10(-5)) and posterior part of the corpus callosum (beta = -15.3 mu L per risk allele, p = 1.23 x 10(-5)), both of which contain temporal lobe commissural tracts. Conclusions: The asymmetric, predominantly left-sided involvement suggests an effect of TMEM106B on functions lateralized to the dominant hemisphere, such as language. These results show that, in nondemented persons, TMEM106B influences the volume of temporal brain regions that are important for language processing.