Genetic reports abstractCR1 genotype is associated with entorhinal cortex volume in young healthy adults
Introduction
Late-onset Alzheimer's disease (AD) is a genetically complex disorder (Bertram et al., 2007). APOE contributes strongly to the heritability of AD (Corder et al., 1993), but the search for other genes has been difficult because of the small individual effect sizes of presumed risk genes. Recently, 2 large genome-wide association studies (GWAS) succeeded in identifying 3 new genes associated with AD: CLU, CR1, and PICALM (Harold et al., 2009, Lambert et al., 2009). However, the mechanisms behind the increase in AD susceptibility caused by these risk genes remain to be explored.
AD is associated with structural changes in the brain starting with anterior medial temporal lobe atrophy centered in entorhinal cortex and hippocampus (Braak and Braak, 1991, Hyman et al., 1984). For APOE, associations have been found between risk genotype and entorhinal and hippocampal volume in AD patients (Geroldi et al., 1999) as well as in healthy individuals (Shaw et al., 2007, Wishart et al., 2006). To investigate whether these AD-related brain regions also mediate the effects of the CLU, CR1, and PICALM risk alleles, we studied brain structure in 2 cohorts of young healthy adults. Structural differences in anterior medial temporal lobe regions, observed as early as in young adulthood, may contribute to the increased susceptibility for AD later in life.
Section snippets
Methods
Detailed description of the methods can be found in the Supplementary methods section. This study is part of the Brain Imaging Genetics (BIG) project running at the Radboud University Nijmegen (Medical Centre). Saliva and structural magnetic resonance imaging (MRI) data were collected from 922 healthy, highly educated (bachelor student level or higher) adults of Caucasian origin between 18 and 36 years of age, with no self-reported neurological or psychiatric history (for demographics see Table
Results
The participant demographics and genotype distributions are shown in Table 1. All genotypes were in Hardy-Weinberg Equilibrium (p > 0.05). Genotyping was successful in 100%, 97.9%, 98.3%, and 98.7% of the samples for CLU, CR1, PICALM, and APOE respectively.
VBM analysis of local gray matter volume in the entorhinal cortex and the hippocampus showed significant differences between genotypes. In the discovery cohort associations between CR1 genotype and local gray matter volume were found in the
Discussion
In this study we investigated associations of 3 recently identified AD risk genes, CLU, CR1, and PICALM with AD-related brain regions in young healthy adults. Whereas for CLU and PICALM no significant associations with local brain volume were found, carriers of the AD risk allele in CR1 showed smaller local gray matter volume in the entorhinal cortex. This finding was confirmed in a second, independent cohort. Dose effect analysis showed significant results, suggesting a possible additive
Disclosure statement
The authors report no conflicts of interest.
All participants gave written informed consent and the study was approved by the local ethics committee.
Acknowledgements
The authors thank all participants who took part in the study. The authors thank R. Makkinje and S. Kooijman for their support in genotyping and recruitment of participants. This project was partly funded by a grant from the Hersenstichting Nederland.
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