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Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.


ABSTRACT: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (A?) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to A?42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A?38 and CSF-A?40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-A? and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

SUBMITTER: Hong S 

PROVIDER: S-EPMC7680793 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.

Hong Shengjun S   Prokopenko Dmitry D   Dobricic Valerija V   Kilpert Fabian F   Bos Isabelle I   Vos Stephanie J B SJB   Tijms Betty M BM   Andreasson Ulf U   Blennow Kaj K   Vandenberghe Rik R   Cleynen Isabelle I   Gabel Silvy S   Schaeverbeke Jolien J   Scheltens Philip P   Teunissen Charlotte E CE   Niemantsverdriet Ellis E   Engelborghs Sebastiaan S   Frisoni Giovanni G   Blin Olivier O   Richardson Jill C JC   Bordet Regis R   Molinuevo José Luis JL   Rami Lorena L   Kettunen Petronella P   Wallin Anders A   Lleó Alberto A   Sala Isabel I   Popp Julius J   Peyratout Gwendoline G   Martinez-Lage Pablo P   Tainta Mikel M   Dobson Richard J B RJB   Legido-Quigley Cristina C   Sleegers Kristel K   Van Broeckhoven Christine C   Ten Kate Mara M   Barkhof Frederik F   Zetterberg Henrik H   Lovestone Simon S   Streffer Johannes J   Wittig Michael M   Franke Andre A   Tanzi Rudolph E RE   Visser Pieter Jelle PJ   Bertram Lars L  

Translational psychiatry 20201122 1


Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better  ...[more]

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