Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

Abstract

IMPORTANCECompared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. OBJECTIVETo identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. DESIGN, SETTING, AND PARTICIPANTSThis genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. MAIN OUTCOMES AND MEASURES Diagnosis of Alzheimer disease.RESULTS A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10 −7 ), near the immune response gene ALCAM (3q13; P = 9.3 × 10 −7 ), within GPC6 (13q31; P = 4.1 × 10 −7 ), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10 −7 ), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10 −9 ) and 6 additional loci with suggestive significance (P Յ 5 × 10 −7 ) such as API5 at 11p12 (P = 8.8 × 10 −8 ) and RBFOX1 at 16p13 (P = 5.4 × 10 −7 ) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.CONCLUSIONS AND RELEVANCE While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

“…More recently, genetic knockdown of heparan sulfate-modifying enzyme hse-5 in C. elegans mitigated TDP-43 induced deficits in synaptic transmission [ 55 ], further suggesting a link between TDP-43 pathology, neurodegeneration and heparan sulfate proteoglycans such as Dlp/GPC6. Lastly, in the last year, genome wide association studies have identified GPC6 as a risk factor multiple sclerosis [ 80 ] and for Alzheimer’s in African Americans [ 51 ] further suggesting a role for GPC6 in maintaining neuronal function.…”

WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders

“…Of relevance to this review, SNP variant rs62039712 (NC_000016.9: g.79355857G>A) mapping to the WWOX locus reached genome-wide significance ( p = 3.7 × 10 −8 ) with an OR of 1.16 [ 10 ]. The identification of WWOX as a novel AD risk gene is further supported by a recently published meta-analysis with the goal of identifying novel AD risk loci in African American individuals [ 60 ]. The authors identified several novel loci of genome-wide significance for individuals of African American ancestry.…”

“…The authors identified several novel loci of genome-wide significance for individuals of African American ancestry. Interestingly, of the 25 previously identified AD loci in non-Hispanic White individuals [ 10 ], WWOX was found among only 7 loci that were implicated at a nominal significance level in African American individuals, suggesting that this gene may participate in cellular pathways associated with AD common to both ancestries [ 60 ].…”

Blood pressure‐related differences in brain health between young African Americans and Caucasian Americans

“…AAs are more likely to experience kidney failure and disease compared to CAs (Harding et al, 2017). Indeed, a recent genome‐wide association meta‐analysis suggested a genetic link between kidney system function and risk of Alzheimer's disease in AAs (Kunkle et al, 2021). Given the strong relationship between kidney function and BP (Young et al, 2002), genetic differences linked with kidney function between the race groups might have been associated with the interaction between race and MAP in the present study.…”