In:
Alzheimer's & Dementia, Wiley, Vol. 16, No. S2 ( 2020-12)
Kurzfassung:
Alzheimer disease (AD) is a neurodegenerative disease, affecting around 5.8 million people in the United States as of 2019. It has been widely studied, but there is still no effective treatment. Using large‐scale Genome‐wide association studies and whole genome/exome sequencing, researchers have identified common and rare variants associated disease risk that can be used to build prediction models. However, there are limited studies that use high‐throughput genomic approaches to identify novel biomarkers beyond genetic variations. Method We profiled 1,305 proteins using SOMAscan platform for 971 CSF, 636 plasma, and 458 parietal lobe from participants of the Knight‐ADRC. We aim to identify the genetic architecture that govern protein levels and how do these proteins modulate AD risk, age at onset, rate of progression, and additional neurodegenerative traits. To do so, we first identified protein quantitative trait loci (pQTLs) from CSF, plasma, and brain tissues. Next, we inferred causality between proteins with significant pQTLs and AD and neurodegenerative traits employing Mendelian Randomization (MR) approaches. Result We identified pQTLs in each tissue. We found 26, 17, and 206 novel pQTLs, in brain, plasma and CSF respectively. We also successfully replicated several reported pQTLs from CSF (e.g. rs2673908 associated with the protein Siglec‐9) and plasma (e.g. rs12740374 associated with the protein Granulins). To infer the causality between proteins and AD or other neurological diseases, we performed MR analysis by using pQTLs as instrumental variables. Overall, we processed MR framework using proteins with significant pQTLs within each tissue on seven neurological‐related traits. Known protein‐disease relationships were replicated. For example, plasma Siglec‐3 (CD33) increases the AD risk, consistent with a larger plasma‐proteome MR analyses by Zheng and colleagues in 2019. We also uncovered the novel proteins in pathways associated with AD risk and additional endophenotypes. In total, we found between 6 to 25 potential new biomarkers for AD progression, depending on the tissue we evaluated. Similarly, we identified 2 to 21 proteins associated with for AD age at onset. Conclusion Taken together, these findings prioritized the proteins for the functional validation study. Thus, the findings helped identify potential biomarkers for AD or other neurological traits.
Materialart:
Online-Ressource
ISSN:
1552-5260
,
1552-5279
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2020
ZDB Id:
2201940-6
