Gene Verification Committee
Gene Verification Committee (GVC).
A large number of publications report genetic evidence that a gene or genetic signal influences or causes AD. The quality of evidence presented in these publications is highly variable. To clarify which loci and genes are valid versus potential false positives, the GVC is reviewing published human genetic studies of AD and dementia to determine the quality of evidence supporting a genetic signal (locus) or a specific gene.
AD therapeutic targets.
Retrospective analyses show that therapeutic targets supported by genetic evidence are 2–3 times more likely to succeed compared with targets not supported by genetic findings1. Thus, genetic gene discovery work for Alzheimer’s disease (AD) and related dementias (ADRD), and dementia are a valid source of therapeutic targets. Developing a gene into a therapeutic target is a resource-intensive process, and it is critical that the genetic evidence supporting a candidate therapeutic target be carefully evaluated.
Contributors for GVC:
- Ryan Corces, Gladstone Institutes
- Anita DeStefano, Boston University
- Lindsay Farrer, Boston University
- Alison Goate, Icahn School of Medicine at Mount Sinai
- Brian Kunkle, University of Miami
- Fanny Leung, University of Pennsylvania
- Edoardo Marcora, Icahn School of Medicine at Mount Sinai
- Richard Mayeux, Columbia University
- Gerard Schellenberg (chair), University of Pennsylvania
- Badri Vardarajan, Columbia University
AD Loci and Gene List (preliminary)
The loci and gene lists are being refined and should be considered a work in progress.
There are 76 loci with genome-wide significant evidence of affecting AD risk (Table 1)2. An AD locus is a small region of the genome where there exists an AD risk/protective gene. A locus may contain several genes that are candidate AD genes. Typically, there is one gene/locus, but possibly more than one in some cases. The Gene Verification Committee (GVC) has reviewed evidence for these loci. They are for the phenotype of clinical/pathologic diagnosed AD or Dementia. Table 1 is a work-in-progress, and as new studies are published, the GVC will evaluate the findings and update the table.
View in Google Sheets.
Table 2 lists causal genes for AD risk or protection. These were identified by a review of the literature by the GVC, pathway analysis2, and by integration of genetic studies with myeloid genomics3.
View in Google Sheets.
Genome-wide association (GWAS) signals.
GWAS signals identify loci, which are regions of the genome where an ADRD/dementia risk or protective gene is present. GWAS studies are a powerful method and have identified a large number of AD-associated loci. However, the region associated with ADRD/dementia may contain several genes, and the actual causative gene is not clearly identified. To evaluate published genetic studies, the GVC performed a structured literature search to select publications to evaluate and develop structured criteria for evaluating genetic associations (Single Variant Rankings – Loci document). A tier system was developed (tier 1–7) to identify the quality of evidence, with tier 1 loci having the highest quality of evidence supporting an association. Table 1 lists 76 unique tier 1 loci with genome-wide evidence of association with AD/dementia2. Table 1 is a work-in-progress, and as new studies are published, the GVC will evaluate the findings and update the table.
Causative AD/dementia genes.
In some cases, the actual causative gene is known or can be inferred using bioinformatic approaches. These genes are located at loci where genome-wide evidence of association or linkage exists. Causative genes are being identified by two processes.
- Expert evaluation of supporting evidence. A list of genes was evaluated by an expert panel that reviewed both genetic and functional evidence. The result was a list of 20 high-confidence genes causative or protective for AD (Table 2, source – GVC). Additional high-confidence genes were identified by evaluating myeloid genomics4. Note that for three of these AD genes (APP, PSEN1, APOE) and one gene from an ADRD disorder (MAPT from PSP studies), the encoded protein has been the target of drug trials for either AD or an ADRD.
- Bioinformatic approaches. More recently, the GVC has begun to use bioinformatic approaches to identify high-confidence causative genes including Open Targets5 and Inferno6 (in progress).
The GVC meets weekly to construct the criteria used and evaluate new publications. The work presented here should be considered a work in progress and may change as additional evidence is reviewed.
Please see the document here on how the criteria is defined: Single Variant Test.
- King, E., et al. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet 15, e1008489 (2019).
- Bellenguez C. et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet, 4, 412-436 (2022).
- Kunkle, B.W., et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet, 51, 414-430 (2019).
- Novikova, G. et al. Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes. Nat Commun, 12, 1610 (2021).
- Mountjoy, E. et al. An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci. Nat Genet, 53, 1527-1533 (2021).
- Amlie-Wolf, A. et al. INFERNO: INFERring the molecular mechanisms of NOncoding genetic variants. Nucl. Acids. Res., 46, 8740-8753 (2018).