Featured publications
CADRE members lead and participate in US and international research consortia. Our goal is to enhance understanding of the genetic architecture of this disease and to accelerate the search for new therapeutic targets. Here we highlight a few recent articles from among the list on our Publications page.
Admixture mapping identifies noval Alzheimer’s disease risk regions in African Americans
FIGURE 3 Admixture mapping Manhattan plot of meta‐analysis African American datasets. Genomic coordinates are displayed along the X‐axis, with each color representing a different chromosome. Negative logarithm of the association p‐value for the ancestral allele is displayed on the Y‐axis. The red dotted horizontal line represents the significance threshold after multiple testing correction, that is, those dots falling above the line are considered study‐wise significant.
Rajabli F, Tosto G, Hamilton-Nelson KL, et al. Admixture mapping identifies novel Alzheimer’s disease risk regions in African Americans. Alzheimers Dement. 2023
Background: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer’s disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.
Methods: We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes.
Results: Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10-5 ) and 18q21.33 (p = 1.2 × 10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2.
Discussion: Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus.
Highlights: We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer’s disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.
DNA from multiple viral species is associated with Alzheimer’s disease risk
FIGURE 1 Frequency of viral reads by tissue source and type of sequencing. Proportion of total viral reads mapping to individual species in (A) whole exome sequence (WES) data from blood, (B) whole genome (WGS) sequence data from blood, (C) WES data from brain in WES, and (D) WGS data from brain. The innermost circle shows the proportion of all viral reads between Alzheimer’s disease (AD) cases and controls within each of these subsets. The middle ring shows the proportion of viral reads mapping to a viral family within AD cases and controls, and the outer ring is the breakdown between viral species within a viral family.
Tejeda M, Farrell J, Zhu C, et al. DNA from multiple viral species is associated with Alzheimer’s disease risk. Alzheimer’s Dement. 2024; 20: 253–265.
Introduction: Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer’s disease (AD) risk by independent lines of evidence. We explored this association by comparing the frequencies of viral species identified in a large sample of AD cases and controls.
Methods: DNA sequence reads that did not align to the human genome in sequenceswere mapped to viral reference sequences, quantified, and then were tested for asso-ciation with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets.
Results: Several viruses were significant predictors of AD according to the machinelearning classifiers. Subsequent regression analyses showed that herpes simplex type1 (HSV-1) (odds ratio [OR] = 3.71, p = 8.03 × 10−4) and human papillomavirus 71(HPV-71; OR = 3.56, p = 0.02), were significantly associated with AD after Bonfer-roni correction. The phylogenetic-related cluster of Herpesviridae was significantlyassociated with AD in several strata of the data (p < 0.01).
Discussion: Our results support the hypothesis that viral infection, especially HSV-1, is associated with AD risk.
An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer’s disease–related patterns
FIGURE 5 TREM2 has the signal region identified in the ADSP WES discovery data set (A) and replicated both in the ADSP WGS replication (B) and the ADSP validation (C) data sets. The signal cluster is identified in the POKEMON test with the DBSCAN algorithm. All variants within the clusters are rare variants with MAF < 0.05. Clusters classified as case clusters are formed by variants carried primarily by AD subjects, and clusters classified as control clusters are formed by variants carried primarily by cognitively normal subjects. Variants assigned with a cluster label are shown, but all the other variants are not shown in the figure.
FIGURE 7 Signal regions on EXOC3L4 (AlphaFold2: Q17RC7.A) are identified by POKEMON from the ADSP WES discovery data set (A) and validated in both the ADSP WGS replication (B) and the ADSP validation (C) data sets. The signal regions are identified in the POKEMON test with the DBSCAN algorithm. All variants within the clusters are rare variants with MAF < 0.05. Clusters classified as case clusters are formed by variants carried primarily by AD subjects and clusters classified as control clusters are formed by variants carried primarily by cognitively normal subjects.
Jin, Bowen et al. “An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer’s disease-related patterns.” Genome research vol. 32,4 (2022): 778-790. doi:10.1101/gr.276069.121
Abstract: More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer’s Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure–based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer’s disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.
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