Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

Abstract

BACKGROUND Genetic loci for Alzheimer disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. METHODS We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer’s Disease Genetics Consortium (ADGC). Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer’s Project (IGAP) GWAS dataset. RESULTS Genome-wide significant (GWS) associations in SNP-based tests (P<5×10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1, and for the interaction of the APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P<2.7×10−6) for gene-based association in the total sample with a novel locus, TPBG (P=1.8×10−6). DISCUSSION Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…In addition, ADAM10, ACE, NYAP1, SPI1, and ECHDC3 were identified through a recent meta‐analysis (Kunkle et al, ). ADAMTS4, HESX1, CLNK, TREM2, CNTAP2, APH1B, KAT8, SCIMP, ABI3, SUZ12P1, ALPK2, and BZRAP‐AS1 were identified with international transethnic cohorts (Jun et al, ) (Table ).…”

“…Analyzing AD brains in a comprehensive and hypothesis-free manner with a combination of various -omics, imaging, and other biomarker analysis techniques has been proposed by the "Alzheimer Precision Medicine Initiative (APMI)" to advance understanding of AD, to identify dysfunctional systems and predictive markers, and to develop remedies against neurodegenerative disorders (Hampel, Toschi, et al, 2018;Hampel, Vergallo, et al, 2018). Genome sequencing projects of human AD patients and meta-analysis of the reports have revealed genes/loci that are frequently mutated in AD patients, that is, AD genetic risk loci (Beecham et al, 2014;Carrasquillo et al, 2015;Chouraki & Seshadri, 2014;Jansen et al, 2019;Kim, 2018;Kunkle et al, 2019;Lambert et al, 2013;Van Cauwenberghe, Broeckhoven, & Sleegers, 2016;Zhang, Gaiteri, et al, 2013), in addition to known familial AD mutations, such as PSEN1/2, APP, and APOE variants. The genes include 21 previously identified loci: ABCA7, BIN1, CASS4, SORL1, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5/HLA-DRB1, INPP5D, MEF2C, MS4M6A, MS4A4E, NME8, PTK2B/PYK2, SLC24A4, and ZCWPW1.…”

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

“…The causes of LOAD are poorly understood, with numerous intrinsic and extrinsic factors believed to influence when the disease occurs and how it progresses. Conventional genetic and genome-wide association studies (GWAS) derived primarily from single-nucleotide polymorphism (SNP) analysis have revealed ~30 loci associated with LOAD [2][3][4][5] , and almost 40% of the total phenotypic variance can be explained by these common SNPs 6 . Translating these genetic findings into biologically meaningful mechanisms of disease pathogenesis and therapeutic interventions remains a huge challenge.…”

Genetics of Alzheimer’s Disease: the Importance of Polygenic and Epistatic Components

“…For example, a GWAS in persons of Korean, Japanese, and Caucasian descent found genome-wide significance with SORL1 [40]. Also, a recent investigation in Europeans, African Americans, Japanese, and Israeli-Arabs found PFDN1/HBEGF , USP6NL / ECHDC3 , and BZEAP1-AS1 were genome-wide significant [41]. …”