Our data suggest that rs2986017 is significantly associated with CSF Aβ42
levels but failed to detect association between CSF Aβ42
levels and SNPs in SORL1
or CSF ptau181
levels and SNPs in GAB2. Giedraitis et al. (2009) failed to detect association between rs2986017 and CSF biomarker levels in a sample of 186 individuals with AD or other cognitive disorders[17
]. This study differs from our study in several important ways. First, the Giedraitis et al study did not include covariates, such as APOE ε4
genotype and CDR, which show strong association with CSF Aβ42
levels in our study () and other studies [40
], in its analyses. Second, power to detect a 1.2-fold increase in CSF Aβ42
levels in the Giedraitis et al was reported to be 0.84. In contrast our study, which included more than three times as many samples, has power of 0.94 to detect a 1.05-fold difference in CSF Aβ42
levels (and power greater than 0.99 to detect a 1.20 fold difference). Finally, CSF Aβ42
levels are decreased in AD cases but not necessarily with other cognitive impairments due to other diseases or disorders. A sample of AD cases is likely to have lower overall CSF Aβ42
levels and less variance in CSF Aβ42
levels than a sample of controls (see ).
Several recent reports failed to detect evidence replicating the initial report of association between risk for LOAD and rs2986017. While our data do not directly address the association with AD risk, they do suggest that the minor allele”, of rs2986017 is significantly associated with higher CSF Aβ42
. This finding is consistent with previous data suggesting that in vitro the “T” allele, which also increases risk for AD, results in increased Aβ42
]. The direction of this association is different from that of the APOE ε4 allele, where carriers show a strong and highly significant decrease in CSF Aβ42 levels, but similar to the effect observed for the PSEN1 A79V Familial AD mutation, where CSF data from a living mutation carrier (clinically unaffected) and findings from in vitro experiments showed significantly increased CSF Aβ42
levels in the presence of the mutation[30
]. At present it is difficult to predict the expected direction of a genetic association with CSF Aβ levels as it appears that those changes may be specific to the risk mechanism of the variant and the point of progression through the disease process.
In 2008, a small study using data from 153 AD cases reported association between CSF Aβ42
levels and SNPs in SORL1
]. A more recent report using CSF from approximately 700 AD cases failed to detect association between CSF Aβ42
and 6 SNPs in SORL1
. Our study, which included CSF from 602 cases and controls, failed to detect evidence for association between SNPs in SORL1
. Power was excellent for an effect of the magnitude detected in CALHM1
(delta=0.60) and 80% power extended down to delta of about half that size. In addition, the inclusion of a large number of controls in our analysis provides much greater variance in Aβ42
levels than a cases-only sample. These calculations suggest it is likely that we would have detected effects of variants in SORL1
on CSF Aβ42
. Unfortunately we did not have measurements of other Aβ species, such as Aβ40
in the ADNI series and therefore could not address the possibility of an effect on other Aβ fragments.
We failed to detect evidence of association between SNPs in GAB2 and ptau181. Power was sufficient (80%) to detect a 1.05 fold difference in the total sample but is poor (0.33) in the APOE ε4 positive subgroup, making it unlikely that we would have detected any effects in this sub-group.
In summary, we have detected marginally significant association between rs2986017, a putative functional SNP within CALMH1, and CSF Aβ42 levels. Our result does not directly address association with risk for LOAD but is consistent with previous reports suggesting that this non-synonymous coding substitution results in increased Aβ levels in vitro. While the signal appears consistent in the combined WU and ADNI datasets, the association is modest and it remains possible that it represents a false positive association. We failed to detect association between SNPs in SORL1 and CSF Aβ42 levels despite substantial statistical power. Both our findings and those of another report from a large CSF sample fail to detect association between SORL1 and CSF Aβ42 levels. This report, along with our previous work further illustrates the possible utility of using CSF endophenotypes to evaluate and understand the biological mechanisms by which variants might modulate risk for AD.