Late-onset Alzheimer’s disease (LOAD) is a devastating neurodegenerative disease with no effective treatment or cure. In addition to APOE, recent large genome-wide association studies have identified variation in over 20 loci that contribute to disease risk: CR1, BIN1, INPP5D, MEF2C, TREM2, CD2AP, HLA-DRB1/HLA-DRB5, EPHA1, NME8, ZCWPW1, CLU, PTK2B, PICALM, SORL1, CELF1, MS4A4/MS4A6E, SLC24A4/RIN3,FERMT2, CD33, ABCA7, CASS4. In addition, rare variants associated with LOAD have also been identified in APP, TREM2 and PLD3 genes. Previous research has identified inflammatory response, lipid metabolism and homeostasis, and endocytosis as the likely modes through which these gene products participate in Alzheimer’s disease. Despite the clustering of these genes across a few common pathways, many of their roles in disease pathogenesis have yet to be determined. In this review, we examine both general and postulated disease functions of these genes and consider a comprehensive view of their potential roles in LOAD risk.
Background The prevalence of obesity and diabetes in Samoa, like many other Pacific Island nations, has reached epidemic proportions. Although the etiology of these conditions can be largely attributed to the rapidly changing economic and nutritional environment, a recently identified genetic variant, rs373863828 (CREB 3 regulatory factor, CREBRF: c.1370G>A p.[R457Q]) is associated with increased odds of obesity, but paradoxically, decreased odds of diabetes. Objective The overarching goal of the Soifua Manuia (Good Health) study was to precisely characterize the association of the CREBRF variant with metabolic (body composition and glucose homeostasis) and behavioral traits (dietary intake, physical activity, sleep, and weight control behaviors) that influence energy homeostasis in 500 adults. Methods A cohort of adult Samoans who participated in a genome-wide association study of adiposity in Samoa in 2010 was followed up, based on the presence or absence of the CREBRF variant, between August 2017 and March 2019. Over a period of 7-10 days, each participant completed the main study protocol, which consisted of anthropometric measurements (weight, height, circumferences, and skinfolds), body composition assessment (bioelectrical impedance and dual-energy x-ray absorptiometry), point-of-care glycated hemoglobin measurement, a fasting blood draw and oral glucose tolerance test, urine collection, blood pressure measurement, hand grip strength measurement, objective physical activity and sleep apnea monitoring, and questionnaire measures (eg, health interview, cigarette and alcohol use, food frequency questionnaire, socioeconomic position, stress, social support, food and water insecurity, sleep, body image, and dietary preferences). In January 2019, a subsample of the study participants (n=118) completed a buttock fat biopsy procedure to collect subcutaneous adipose tissue samples. Results Enrollment of 519 participants was completed in March 2019. Data analyses are ongoing, with results expected in 2020 and 2021. Conclusions While the genetic variant rs373863828, in CREBRF, has the largest known effect size of any identified common obesity gene, very little is currently understood about the mechanisms by which it confers increased odds of obesity but paradoxically lowered odds of type 2 diabetes. The results of this study will provide insights into how the gene functions on a whole-body level, which could provide novel targets to prevent or treat obesity, diabetes, and associated metabolic disorders. This study represents the human arm of a comprehensive and integrated approach involving humans as well as preclinical models that will provide novel insights into metabolic disease. International Registered Report Identifier (IRRID) RR1-10.2196/17329
Late-onset Alzheimer's disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to investigate potential regulatory functions of lead single nucleotide polymorphisms (SNPs) identified in five genome-wide association studies (GWAS) of risk and age-at onset (AAO) of LOAD, as well as SNPs in LD (r2≥0.80) with the lead GWAS SNPs. Of a total 614 SNPs examined, 394 returned RegulomeDB scores of 1–6. Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score <3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/rs1476679, CLU/rs1532278 and ABCA7/rs3764650). This study further supports the assumption that some of the non-coding GWAS SNPs are true associations rather than tagged associations and demonstrates the application of RegulomeDB to GWAS data.
Over twenty risk loci have been identified for late onset Alzheimer’s disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4,567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (OR=7.40, P=3.66E-06). In addition to AD risk, we also examined the association of R47H with AD-related phenotypes, including age-at-onset, psychosis, and amyloid deposition, but found no significant association. Our results corroborate those of other studies implicating TREM2 as a LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration.
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