Genetics of Neurodegeneration
The goal of our research is to identify genetic factors that modulate the risk for neurodegenerative diseases, with a focus on Alzheimer’s disease (AD). Our lab invests on large-scale comparisons of genetic data between AD cases and non-demented controls. We invest in large GWAS studies, and we currently lead the largest international genetic sequencing studies of Alzheimer disease cases and control studies. Furthermore, we invest in AD case control studies using novel sequencing methods such as long read sequencing, which will allow us, for the first time to identify important repeat sequences associated with an increased risk of AD.
MAF (x-axis) is the frequency at which a non-reference (variant) allele occurs in the population. Variant carriers with OR=1 and non-carriers have the same odds of developing Alzheimer’s disease, variants with OR >1 are associated with an increased risk of Alzheimer’s disease, and variants with OR <1 are associated with a protective effect (y-axis). (A) Causative or strong risk increasing variants. A schematic representation of individual rare variants for which ORs cannot be estimated due to extreme variant rareness. Linkage studies in large pedigrees indicate that specific rare variants in PSEN1, PSEN2, and APP cause autosomal dominant Alzheimer’s disease, in some cases with age at onsets as early as 40 years old. Note that not all variants in these three genes give rise to autosomal dominant Alzheimer’s disease; some might be risk-modifiers or non-pathogenic. Further, evidence is accumulating that certain variants in the SORL1 gene are causative of Alzheimer’s disease before the age of 70 years. The Alzheimer’s disease-association of variants in the SORL1, ABCA7, and TREM2 genes was found in gene-based tests; carriers may come from small pedigrees with inheritance patterns of Alzheimer’s disease suggestive of autosomal dominant inheritance. (B) GWAS hits are common (by convention, MAF >1%) variants that represent risk alleles that occur with significantly different frequency in patients with Alzheimer’s disease and controls. Each variant is represented by the gene in which it occurs, or when the variant is non-coding, by the gene that maps closest to the variant (depicted in dark grey). (C) Protective variants are (very) rare variants suggested to confer resistance against age-associated or disease-associated risk factors of cognitive decline. GWAS=genome-wide association studies. MAF=minor allele frequency. OR=odds ratio. PRS=polygenic risk scores.
Collaborations with Longitudinial Aging Study Amsterdam (LASA, Prof. Dr. Martijn Huisman), Amsterdam Dementia Cohort (ADC, Prof. Dr. Wiesje vd Flier), and European Alzheimer’s Disease Database (EADB, Jean Charles Lambert). To investigate polygenic risk scores associated with Alzheimer’s disease and other aging related diseases we generated GWA (genome wide array) data from all centenarians. We compare the centenarian-genomes with middle aged population controls and Alzheimer patients. This led to the first indications that centenarians were enriched with protetive genetic variants and depleted with risk-increasing genetic variants. We are currently expanding these findings towards other aging-related diseases.
Exome sequencing studies
As a partner of the European ADES consortium and in collaboration with the US-based AD sequencing project (ADSP), our lab leads the joint analyses of the DNA sequencing data from AD patients and cognitively healthy controls. To make this possible, we closely collaborate with the Netherlands Supercomputer facility, SURFsara.
Next to mutations in PSEN1, PSEN2 and APP, mutations in the SORL1 gene can lead to a greatly increased chance of developing Alzheimer’s Disease. SORL1 is involved in the production and processing of Alzheimer proteins that accumulate in the brain. The aim of this project is to investigate the effect of SORL1-mutations on the production and accumulation of Alzheimer proteins in the patient brain.
Long read sequencing studies: Structural Variants and repeat sequences
In collaboration with PacBio (USA) and Prof. Marcel Reinders (TU Delft), Dr. Frank Jacobs (SILS), our lab has invested in the long-read sequencing technology to investigate which repetitive sequence lengths and sequence associated with AD. In the near future (2021-2024) we aim to sequence 300 centenarians and 300 AD patients, who represent the extremes on the cognitive spectrum. This will provide a unique dataset world-wide.