The association of GNB5 with Alzheimer disease revealed by genomic analysis restricted to variants impacting gene function

• Published in: American journal of human genetics 2024-03, Vol.111 (3), p.473-486
• Main Authors: Zhang, Jianhua, Pandey, Mritunjay, Awe, Adam, Lue, Nicole, Kittock, Claire, Fikse, Emma, Degner, Katherine, Staples, Jenna, Mokhasi, Neha, Chen, Weiping, Yang, Yanqin, Adikaram, Poorni, Jacob, Nirmal, Greenfest-Allen, Emily, Thomas, Rachel, Bomeny, Laura, Zhang, Yajun, Petros, Timothy J., Wang, Xiaowen, Li, Yulong, Simonds, William F.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Amyloid beta-Peptides - genetics; amyloid plaque; amyloid precursor protein; Animals; APP; Brain - metabolism; G protein; G protein-coupled receptor; Genome-Wide Association Study; Genomics; GPCR; GTP-Binding Protein beta Subunits - genetics; GTP-Binding Protein beta Subunits - metabolism; GWAS; Humans; Lodder-Merla syndrome; Mice; neurofibrillary tangle; Neurofibrillary Tangles - metabolism; Phenotype; RGS protein; Solute Carrier Family 22 Member 5 - genetics; Solute Carrier Family 22 Member 5 - metabolism
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2024.01.005

Disease-associated variants identified from genome-wide association studies (GWASs) frequently map to non-coding areas of the genome such as introns and intergenic regions. An exclusive reliance on gene-agnostic methods of genomic investigation could limit the identification of relevant genes associated with polygenic diseases such as Alzheimer disease (AD). To overcome such potential restriction, we developed a gene-constrained analytical method that considers only moderate- and high-risk variants that affect gene coding sequences. We report here the application of this approach to publicly available datasets containing 181,388 individuals without and with AD and the resulting identification of 660 genes potentially linked to the higher AD prevalence among Africans/African Americans. By integration with transcriptome analysis of 23 brain regions from 2,728 AD case-control samples, we concentrated on nine genes that potentially enhance the risk of AD: AACS, GNB5, GNS, HIPK3, MED13, SHC2, SLC22A5, VPS35, and ZNF398. GNB5, the fifth member of the heterotrimeric G protein beta family encoding Gβ5, is primarily expressed in neurons and is essential for normal neuronal development in mouse brain. Homozygous or compound heterozygous loss of function of GNB5 in humans has previously been associated with a syndrome of developmental delay, cognitive impairment, and cardiac arrhythmia. In validation experiments, we confirmed that Gnb5 heterozygosity enhanced the formation of both amyloid plaques and neurofibrillary tangles in the brains of AD model mice. These results suggest that gene-constrained analysis can complement the power of GWASs in the identification of AD-associated genes and may be more broadly applicable to other polygenic diseases. Nine genes that potentially enhance the risk of Alzheimer disease (AD) were identified using a novel gene-constrained analytical method. One gene encoded heterotrimeric G protein beta family member GNB5. In AD model mice, Gnb5 heterozygosity enhanced the development of AD neuropathology. This method may be applicable to other polygenic diseases.