Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114

GENETIC COMPLEXITY AND RARE VARIANTS IN NEURODEGENERATIVE BRAIN DISEASES

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
04:15 PM - 04:30 PM

Abstract

Abstract Body

Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. Large numbers of rare genetic variants of uncertain significance in coding regions are highlighting the genetic complexity of NBD. We identified several families with autosomal dominant segregation but missing the underlying genetics. In two families, we were able to pinpoint the genetic defect in DDP6 and TRL9, namely rare variants in DPP6 and TLR9 co-segregating with disease. The presence of the mutation lead to loss of the DPP6 and TLR9 proteins. In other families we identified rare variants in major risk genes that were co-segregation with disease in an autosomal dominant manner, for example in ABCA7 and GRN leading to loss of their proteins. Novel findings in the NBD genetic etiology and the impact of rare variants influence NBD pathophysiology. A better understanding of rare variants is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD, and new knowledge might open avenues for effective personalized therapies.

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INTEGRATIVE CO-METHYLATION NETWORK ANALYSIS IDENTIFIES NOVEL DNA METHYLATION SIGNATURES AND THEIR TARGET GENES IN ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
04:30 PM - 04:45 PM

Abstract

Aims

DNA methylation is a key epigenetic marker, and its alternations may be involved in Alzheimer’s disease. CpG sites sharing similar biological functions or pathways tend to be co-methylated.

Methods

We performed an integrative network-based DNA methylation analysis on two independent cohorts (N=941) using brain DNA methylation profiles and RNA-Seq as well as AD pathology data.

Results

Weighted co-methylation network analysis identified six modules as significantly associated with neuritic plaque burden. Fifteen hub CpG sites including three novel CpGs were identified and replicated as being significantly associated with AD pathology. Furthermore, we identified and replicated four target genes (ATP6V1G2, VCP, RAD52, LST1) as significantly regulated by DNA methylation at hub CpG sites. In particular, VCP gene expression was also associated with AD pathology in both cohorts.

Conclusions

This integrative network-based multi-omics study provides compelling evidence for a potential role of DNA methylation alternations and their target genes in Alzheimer’s disease.

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EXOME SEQUENCING IDENTIFIES RARE DAMAGING VARIANTS IN THE ATP8B4 AND ABCA1 GENES AS NOVEL RISK FACTORS FOR ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
04:45 PM - 05:00 PM

Abstract

Aims

Using exome-sequencing strategies, rare damaging variants in the TREM2, SORL1 and ABCA7 genes were previously associated with a strong increased risk of developing Alzheimer’s Disease (AD). To identify additional AD-associated genes, we investigated the burden of rare damaging variants in the exomes of AD cases and controls.

Methods

We analyzed sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Detected non-synonymous and loss-of-function rare variants were prioritized by REVEL and LOFTEE, and the gene-based burden of rare variants was compared for the 13,222 genes that had at least 10 predicted damaging variants in our dataset.

Results

Next to SORL1, TREM2, ABCA7, we newly identified an AD-association of rare damaging variants in the ATP8B4 and ABCA1 genes (both phospholipid transporters). In addition, we found a strong indication for the AD-association of ADAM10 and SRC genes (both involved in APP processing). Also, our analysis highlighted RIN3, CLU, ZCWPW1 and ACE as potential causal genes in AD-GWAS loci (all involved in APP/Aβ processing, except ZCWPW1). High-impact variants in these genes, in particular loss-of-function variants, are mostly extremely rare and enriched in AD patients with early ages at onset (Figure).

Conclusions

We newly identified genes in which rare high-impact variants have a large effect on the risk of AD. The strong association of LOF variants suggests that reduced activity of these genes increases AD risk. These genes provide additional evidence for a major role for APP-processing, Aβ-aggregation and microglial function in AD.

holstege_ades_figure.jpg

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GENOME-WIDE ASSOCIATIONS FOR ALZHEIMER RELEVANT CEREBROSPINAL FLUID AMYLOID AND TAU PROTEIN LEVELS

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
05:00 PM - 05:15 PM

Abstract

Aims

Measurable biological properties can be more strongly related to the underlying Alzheimer’s disease (AD) pathogenesis than clinical diagnosis. We therefore studied the genetics of amyloid-beta and phosphorylated tau concentrations in cerebrospinal fluid (CSF).

Methods

Initiated by the European Alzheimer’s and Dementia biobank (EADB), we established the largest collaborative effort on genetics underlying CSF biomarkers, including 31 cohorts with a total of 13,118 individuals combining the discovery (EADB) and replication steps (US-based cohorts).

Results

As expected APOE was associated with the level of both CSF amyloid beta and pTau. Besides APOE, we describe for the first time the association of the well-established AD locus CR1 with CSF amyloid beta me, as well as the association of BIN1 with CSF pTau. For pTau, two novel loci (GMNC and C16orf95) were identified that had not been identify in the latest AD case-control GWAS. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories (amyloid, astrocyte, processing & migration, and migration & motility) suggesting multiple biological pathways involved in the etiology of amyloid and tau pathology in dementia. In a functional follow-up analysis, we found that GMNC and C16orf95 both associate with lateral ventricular volume, implying an overlap in genetic etiology for tau and brain ventricular volume.

Conclusions

Genetic effects of amyloid-beta and phosphorylated tau reveals novel associations, and highlight important biological insights into AD.

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LINKAGE ANALYSES CONFIRM CHROMOSOME 5Q35 AS A RISK LOCUS IN AFRICAN ANCESTRY POPULATION.

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
05:15 PM - 05:30 PM

Abstract

Aims

In this study, we performed whole-genome sequencing (WGS) in multi-generational AA Alzheimer disease (AD) families from the Research in African American AD Initiative (REAAADI) and Late-Onset AD Family Study (LOAD) to identify rare causal variants influencing AD through linkage and segregation-based approaches.

Methods

As part of REAAADI and LOAD, genotyping array and WGS data were generated for 51 families (160 affected and 318 unaffected). We performed a multipoint linkage scan using MERLIN software and genotype data to identify the genetic loci likely to carry risk variants. Next, WGS data were used to prioritize variants in the consensus regions (HLOD > 3) based on segregation with disease among affected individuals, rarity (MAF<0.01), and annotation for putative function (CADD > 5).

Results

The peak lod score was on Chromosome 5q35 (HLOD=3.20). 1-LOD region is flanking with the locus that was previously reported as a suggestive significant locus in GWAS studies on AD in AAs conducted by the ADGC (p-value=2.6 × 10-6). Segregation analysis using WGS data, identified 6 rare variants (MAF<0.01) with the CADD score > 5 that segregated with disease in all affected individuals of the family with the highest LOD score contributing to the linkage peak.

Conclusions

Our AA population-specific finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale.

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MAPPING THE MULTIFACTORIAL GENETIC LANDSCAPE OF EARLY-ONSET ALZHEIMER’S DISEASE IN A COHORT OF 37 FAMILIES

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
05:30 PM - 05:45 PM

Abstract

Aims

Many families with early-onset Alzheimer’s disease (EOAD) remain genetically unresolved. A combination of genetic factors is not standardly investigated. In this study, we evaluated the possible multifactorial etiology in a large series of families, to assess if clinical genetic testing could be expanded.

Methods

We performed exome sequencing and SNP arrays of 37 families (79 patients) including at least one patient with symptom onset before 70 years. We evaluated segregating rare variants in known dementia genes according to ACMG guidelines, and other genes/variants if shared by multiple families. We computed APOE genotypes and AD polygenetic risk scores compared to a reference population dataset (PRS z-scores).

Results

Eight families carried a pathogenic variant and we identified eight variants of uncertain significance (VUS) in dementia related genes, including ABCA7, SORL1, and a novel SQSTM1 nonsense variant. Out of the 79 patients, 33 (42%) were APOE-ε4 heterozygous and 28 (35%) homozygous. In families with VUS, 9/16 patients (56%) were APOE-ε4 homozygous. The PRS of the families was insignificantly increased compared to the population (average PRSz=0.2), and did not clearly correlate with other factors (e.g. pathogenic variant, APOE-ε4 burden). However, one family had a remarkably high score (PRSz=3.4).

Conclusions

Besides a monogenetic cause in 20%, we highlight six families with the combination of APOE-ε4 and VUS as likely cause of disease. The extreme PRS in one family might cause polygenic AD, though this needs to be replicated. We propose that APOE, VUS in dementia genes, and PRS are implemented in diagnostic testing of unresolved familial EOAD.

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TRANSCRIPTOME- AND PROTEOME-WIDE ASSOCIATION STUDIES OF PARKINSON’S DISEASE IDENTIFY PATHWAYS INVOLVED IN DISEASE ETIOLOGY

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
05:45 PM - 06:00 PM

Abstract

Aims

Over 100 loci have been implicated in the pathogenesis of idiopathic Parkinson’s disease (PD) from Genome-Wide Association Studies (GWAS). However, functional information about the transcript or protein levels of PD-associated genes in disease-specific tissues is largely lacking. Hence, we conducted a Transcriptome Wide Association Study (TWAS) and a Proteome Wide Association Study (PWAS) to identify transcripts and proteins that mediate GWAS risk.

Methods

We combined summary statistics from the latest PD GWAS (Nalls et al., 2019), with brain-specific expression quantitative trait loci (eQTL) from 888 neocortical samples (Gockley et al., 2021) in the discovery stage of TWAS. The replication TWAS used eQTL data from 1,433 prefrontal cortex (PFC) samples (Sieberts et al., 2020). Similarly, we combined the PD GWAS summary statistics with two protein-QTL studies, Religious Orders Study and Rush Memory and Aging Project (ROS/MAP, n = 330 PFC samples), and Banner Sun Health Brain and Body Donation Program (Banner BBDP, n = 149 PFC samples). TWAS and PWAS were conducted using the FUSION framework.

Results

We identified 66 genes significant by the TWAS analyses and 39 proteins by the PWAS analyses (both at FDR of 10%). We tested for enrichment of pathways for our combined set of 76 significant genes and identified enrichment for pathways such as the SNARE interactions in vesicular transport (enrichment = 16.8-fold), and the lysosome pathway (enrichment = 7.8-fold).

Conclusions

Our study represents the largest TWAS and PWAS analyses to date for Parkinson’s disease. The genes we identified further refine key biological pathways important to PD etiology.

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PRE-RECORDED: EXPANDING ROLE OF MICROSATELLITE REPEATS IN NEURODEGENERATIVE DISEASE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
04:15 PM - 06:15 PM
Room
ONSITE: 114
Lecture Time
06:00 PM - 06:15 PM

Abstract

Abstract Body

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease. While intense research efforts on known genetic forms of ALS have led to important molecular insights and the development of potentially life-changing drugs, these mutations do not explain disease in most ALS cases. In fact, nearly 90% of ALS patients present as sporadic case (sALS) with unknown genetic etiology. This lack of knowledge represents a significant barrier for disease management and the development of effective therapies. By far the most frequent, known, genetic cause of sALS is the C9orf72 G4C2 repeat expansion and there is strong evidence that toxic repeat-associated non-AUG (RAN) proteins contribute to this disease. We now show novel polySer and polyLeu RAN proteins accumulate in spinocerebellar ataxia types 1, 2, 3, 6 and 7 autopsy brains (n>4 cases / disease). Additionally, we detect multiple types of RAN proteins in tissues from sALS patients with unknown genetic etiology, implicating novel repeat expansion mutations as an important contributor to sALS. Finally, we have developed an innovative dCas9-based tool (dCas9READ) that enables the direct enrichment and identification of repeat expansion loci from single genomic DNA samples. Identifying novel expansion mutations for sALS and other genetically unknown neurological diseases will enable additional genetic testing and facilitate the development of novel biomarkers and drugs to fight these disorders.

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