Iris E. Jansen, Netherlands
Center for Neurogenomics and Cognitive research, VU University Department of Complex Trait GeneticsAuthor Of 1 Presentation
FUNCTIONAL INTERPRETATION OF GENETIC RISK LOCI FOR DEMENTIA USING A PROTEIN QUANTITATIVE TRAIT LOCI (PQTLS) APPROACH IN CEREBROSPINAL FLUID
Abstract
Aims
Exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. To reveal intermediate molecular pathways connecting genetic variance to development of dementia, we aimed to identify protein quantitative trait loci (pQTLs) in cerebrospinal fluid (CSF) in Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).
Methods
We included 503 subjects for discovery (146 controls, 214 AD, 50 DLB, 93 FTD) and 99 for validation from the Amsterdam Dementia Cohort, from which genetics (Illumina Genome Screening Array) and CSF proteomics (n=665, ligand-proximity immunoarrays) was available. Association signals between risk loci and CSF proteins were tested using linear regression with Bonferroni correction, adjusted for principal components, age and sex and stratified by diagnosis.
Results
Three AD and one DLB risk loci were associated with levels of seven CSF proteins (Figure 1). CR1 locus associated with higher CR2 (Pdiscovery=5.47e-7, Preplication=1.66e-3), ZCWPW1 with lower PILRB (Pdiscovery=2.73e-32, Preplication=7.82e-8) and HESX1 with higher RETN CSF levels (Pdiscovery=6.00e-8, Preplication=0.01); proteins related to the immune system and glucose metabolism. DLB locus GBA associated with higher CSF protein levels of ANG, CD79B, CXCL13 and TNFRSF13B (all Pdiscovery<1.00x10-8); proteins associated to angiogenesis and immune response. FTD risk loci did not significantly associate with CSF proteins.
Conclusions
The four pQTLs identified suggest that specific risk loci for AD and DLB may contribute to the pathogenesis of these dementias by exerting effects on the immune system, glucose metabolism and angiogenesis. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying different types of dementia.