Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifiesLRRC4C, LHX5-AS1and nominates ancestry-specific lociPTPRK,GRB14, andKIAA0825as novel risk loci for Alzheimer’s disease: the Alzheimer’s Disease Genetics Consortium

Abstract

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways

“…This study does have some weaknesses that need to be acknowledged. Firstly, despite a similar sample size and single variant analysis model to the work done by Rajabli et al, 24 , this study identi ed more novel associations with AD. Given the limited availability of large-scale EOAD analyses for comparison, it is challenging to entirely dismiss the possibility of false positives arising a consequence of our study design.…”

“…To put our trans-ancestry results in context with more recent ndings and assess our hypothesis, we can compare our ndings and conclusions with transancestry LOAD analyses by Lake et al, 25 and Rajabli et al, 24 . Lake et al, were able to identify two novel trans-ancestry LOAD loci by meta-analysis of summary statistics from ve recent LOAD GWASs; from Bellenguez 18 , FinnGen Release 6 (https://www.…”

“…This may implicate this family of genes as having important latent functions which impact AD. Additionally, previous studies implicate insulin receptor activity regulation by GBR14 24 . This is in line with our ndings of a relationship between ELL and myo-inositol in EOAD (Table S17), as myo-inositol also modulates insulin-mediated signaling.…”

An Alzheimer’s disease-associated common regulatory variant in PTK2B has causal effects on microglial function

“…This pathway is activated by Aβ in microglia, where PTK2B is autophosphorylated and generates a positive feedback loop to further activate TRPM2 [69]. PTK2B has been implicated in AD through a number of GWAS studies [4,6,[70][71][72][73][74][75][76][77]. As well as being involved in response to Aβ, PTK2B co-localizes with hyperphosphorylated Tau in the brain of AD patients and in a mouse model, and it may contribute to Tau phosphorylation [78,79].…”

Editorial: Genetics and biomarkers of Alzheimer's disease in Asian populations

“…Considering these differences, alternative genetic risk factors might play a role in the development of AD in these populations. A recent transethnic AD genome-wide association study identified ancestry-specific loci, underscoring the need for more research into non-European populations' genetics, biomarkers, and mechanisms (Rajabli et al, 2023 ).…”