14 January 2015
We read with interest the article by Hernández et al. on the TMEM106B genetic variant rs1990622 that modifies the risk for frontotemporal dementia (FTD) . Although the authors were underpowered to detect a significant association with FTD risk in their case-control study (n/N=146/381), the effect was concordant with the expected direction and slightly decreased in p-value under a recessive model. Similarly, meta-analysis of published data was more significant assuming a recessive effect for the rs1990622 CC genotype.
Previously we showed that the additive effect of rs1990622 is not restricted to FTD but that this variant also affects brain structure in the general population free of dementia . Given the findings of Hernández et al. , we aimed to determine whether this recessive model also holds for the association of rs1990622 in the general population. In line with our previous publication, we investigated this question in 4,413 non-demented and stroke-free participants from the population-based Rotterdam Study who underwent both genotyping and magnetic resonance imaging [3-4]. The eight brain structures that previously survived multiple testing correction were analyzed under three different models: additive (as published), recessive, and dominant. All analyses were adjusted for age and sex.
As shown in Table 1, associations under both the recessive and dominant model were either in the same order of magnitude or less significant than the additive model. This does not support the notion of a recessive effect, as found by Hernández et al. , in our population-based sample in which we investigated brain structure. Rather, it seems to suggest that each T allele increase confers an additional risk. We agree with the authors that larger studies will provide us the definitive answer with regard to the genetic model under which rs1990622 predisposes to FTD.
Hieab H.H. Adams, Meike W. Vernooij, and M. Arfan Ikram
Departments of Epidemiology and Radiology, Erasmus MC, Rotterdam, The Netherlands
 Hernández I, Rosende-Roca M, Alegret M, Mauleón A, Espinosa A, Vargas L, Sotolongo-Grau O, Tárraga L, Boada M, Ruiz A (2015) Association of TMEM106B rs1990622 marker and frontotemporal dementia: evidence for a recessive effect and meta-analysis. J Alzheimers Dis 43, 325-334.
 Adams HH, Verhaaren BF, Vrooman HA, Uitterlinden AG, Hofman A, van Duijn CM, van der Lugt A, Niessen WJ, Vernooij MW, Ikram MA (2014) TMEM106B influences volume of left-sided temporal lobe and interhemispheric structures in the general population. Biol Psychiatry 76, 503-508.
 Hofman A, Darwish Murad S, van Duijn CM, Franco OH, Goedegebure A, Ikram MA, Klaver CC, Nijsten TE, Peeters RP, Stricker BH, Tiemeier HW, Uitterlinden AG, Vernooij MW (2013) The Rotterdam Study: 2014 objectives and design update. Eur J Epidemiol 28, 889-926.
 Ikram MA, van der Lugt A, Niessen WJ, Krestin GP, Koudstaal PJ, Hofman A, Breteler MM, Vernooij MW (2011) The Rotterdam Scan Study: design and update up to 2012. Eur J Epidemiol 26, 811-824.