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Genome‐wide association study of progression in Alzheimer's disease
Author(s) -
Katzourou Ioanna,
Leonenko Ganna,
Williams Julie,
Holmans Peter,
EscottPrice Valentina
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.040950
Subject(s) - genome wide association study , bonferroni correction , apolipoprotein e , disease , multiple comparisons problem , genetic association , medicine , oncology , single nucleotide polymorphism , genotype , genetics , biology , statistics , gene , mathematics
Background The rate of disease progression is an important factor to consider regarding Alzheimer’s disease (AD), as people with a rapid decline are considerably more likely to require additional care resources. The rate of progression in AD has been found to vary widely between individuals, with numerous factors driving this heterogeneity. In this project, a genome‐wide association study (GWAS) was performed to investigate the presence of a genetic liability to faster progression in patients with AD. Methods A subset of 543 individuals with AD from the Cardiff MRC centre cohorts that have been assessed at multiple timepoints was used in this analysis. A progression score for each individual was approximated by a random slope from a random effects regression model of Mini Mental State Examination (MMSE) using all available MMSE measurements. The score was subsequently used in a GWAS of progression. Quality control analysis was performed following standard GWAS protocols resulting in 304,448 variants to be included in the analysis. Results The sample was 67.37% female, with mean age at recruitment being 80.2 years. Mean MMSE was 17.03 at first assessment and 11.54 at last assessment, and mean number of assessments was 3.16. After correcting for multiple testing, no variant was found to be significantly associated with progression in this GWAS. Furthermore, apolipoprotein E ( ApoE ) genotype was not associated with progression. Conclusion Preliminary results show that, after Bonferroni correction for multiple testing, no variant was significantly associated with progression in AD. Suggestive associated variants were found in chromosome 20:5843812 (p‐value = 3.12 × 10 −7 ), 1:62271962 (p‐value = 6.30 × 10 −7 ), 10:15452800 (p‐value = 1.65 × 10 −6 ) and 5:117646945 (p‐value = 2.40 × 10 −6 ). Moreover, ApoE genotype was not found to affect the rate progression, the lowest p‐value in the ApoE region (19:44905791 ‐ 19:44909393) being 0.23. This non‐significant result might indicate that the genetic risk for accelerated cognitive decline within AD is separate from the genetic risk for developing AD. The sample size is one of the main limitations of this study. Replication in a larger dataset is necessary in order to validate these findings and uncover the presence of genetic variants that affect the rate of decline in AD.