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Novel genetic effects on amyloid and tau protein levels in cerebrospinal fluid
Author(s) -
Jansen Iris E.,
Van Der Lee Sven J.,
Bellenguez Céline,
GrenierBoley Benjamin,
de Rojas Itziar,
Zettergren Anna,
Kleineidam Luca
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.037973
Subject(s) - locus (genetics) , apolipoprotein e , dementia , biomarker , genetics , biobank , population , biology , genome wide association study , alzheimer's disease , disease , medicine , genotype , single nucleotide polymorphism , gene , environmental health
Background Assuming measurable biological properties to be more strongly related to the underlying Alzheimer’s disease (AD) pathogenesis than the diagnostic classification, we studied the genetics of AD‐relevant protein levels in cerebrospinal fluid (CSF). Initiated by the European Alzheimer’s disease DNA biobank (EADB), we established the largest collaborative effort on CSF amyloid beta and tau, and aimed to improve the current understanding on the genetic etiology of AD, including the identification of novel genetic risk factors. Method A collection of 10 European dementia cohorts was explored to study the genetic effects on CSF amyloid beta (n = 6529 individuals), tau (n = 6455 individuals) and phosphorylated tau (n = 5865). Most of the genetic data was generated with Illumina Global Screening Array, and imputed with TOPMed reference genome. The protein level data was log transformed and normalized. Per variant linear regressions were performed within cohorts using PLINK v2.0, followed by meta‐analysis. We corrected for population structure (principal components), gender, age and biomarker assay type (if applicable within a cohort). Results Besides APOE ( p = 3.16 × 10 −251 ), no other loci reached genome‐wide significance for amyloid beta protein levels. For tau protein levels, we discovered 5 loci, including the known AD loci APOE ( p = 1.61 × 10 −61 ) and HLA‐DRB1 ( p = 4.67 × 10 −8 ). We additionally confirm the GMNC locus ( p = 1.23 × 10 −12 ) that previously was associated with CSF tau by an independent consortium. Two novel loci are seen on chromosome 9 ( p = 5.76 × 10 −8 ) and chromosome 16 ( p = 3.67 × 10 −8 ). These tau findings are strengthened by the identification of these same 5 loci for phosphorylated tau which has been measured by a different protein level assay. Both novel loci have shown associations with brain ventricular volume in previous large‐scale studies performed by other consortia, such as CHARGE and ADNI. Conclusion The novel loci identified for CSF tau protein levels suggest an overlap in genetic etiology for tau and brain ventricular volume, thereby strengthening the theory that neurodegeneration and tau pathology are highly correlated in dementia patients.