There is little information on the association of the APOEe4 allele and AD risk in African populations. In previous analyses from the Indianapolis-Ibadan dementia project, we have reported that APOE ...epsilon 4 increased the risk for Alzheimer's disease (AD) in African Americans but not in Yoruba. This study represents a replication of this earlier work using enriched cohorts and extending the analysis to include cognitive decline. In this longitudinal study of two community dwelling cohorts of elderly Yoruba and African Americans, APOE genotyping was conducted from blood samples taken on or before 2001 (1,871 African Americans & 2,200 Yoruba). Mean follow up time was 8.5 years for African Americans and 8.8 years for Yoruba. The effects of heterozygosity or homozygosity of epsilon 4 and of the possession of e4 on time to incident AD and on cognitive decline were determined using Cox's proportional hazards regression and mixed effects models. After adjusting for covariates, one or two copies of the APOE epsilon 4 allele were significant risk factors for incident AD (p < 0.0001) and cognitive decline in the African-American population (p < 0001). In the Yoruba, only homozygosity for APOE epsilon 4 was a significant risk factor for AD (p = 0.0002) but not for cognitive decline (p = 0.2346), however, possession of an e4 allele was significant for both incident AD (p = 0.0489) and cognitive decline (p = 0.0425). In this large longitudinal comparative study, APOE epsilon 4 had a significant, but weaker, effect on incident AD and on cognitive decline in Yoruba than in African Americans. The reasons for these differences remain unclear.
Background
African ancestry populations have a lower risk for developing Alzheimer disease (AD) from ApoEε4 compared to other populations. Understanding this mechanism of protection could lead new ...therapeutic insights for AD. Our goal is to identify areas of the genome that interact with ApoEε4 in African ancestry that result in the lowered risk for developing AD in this population.
Methods
We performed association analyses using a logistic regression model with ApoEε4 allele as an interaction term and adjusted for genome‐wide ancestry, age, and sex. Discovery analysis included imputed SNP data from 1,850 African American (AA) individuals with AD and 4,331 AA controls. We performed replication analysis on whole‐genome sequenced (WGS) data from 1) 63 Ibadan (Nigerian) AD individuals and 648 Ibadan controls; 2) WGS 273 Puerto Rican (PR) AD individuals and 275 PR controls; and 3) SNPs imputed from 8,463 non‐Hispanic White (NHW) AD individuals and 11,365 NHW controls.
Results
We identified a significant interaction with the ApoE ε4 allele and the SNP rs10423769_A allele, that reduces the odds ratio for AD risk from 7.2 for ApoEε4/ε4 without the A allele to 2.1 for allele ApoEε4/ε4 carriers with at least one A allele. rs10423769 (frequency = 0.11 in AA, NHW= 0.003) is located approximately 2 megabases distal to ApoE, in a large cluster of pregnancy specific beta‐1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. rs10423769 is reported to be a splicing QTL (sQTL) for TMEM145, whose highest brain expression is in the cerebellum. This interaction analysis was identified in the discovery AA dataset (β=‐0.54, SE=0.12,p‐value=7.50x10‐6), and this finding was replicated in both the Ibadan (β = ‐1.32,SE = 0.52,p‐value = 1.15x10‐2) and PR (β=‐1.27,SE=0.64,p‐value=4.91x10‐2) datasets while it trended but was not significant in the NHW dataset.
Conclusion
This study identified a new African‐ancestry specific locus that reduces the risk effect of ApoEε4 for developing AD by approximately 75%. The genes lying near this protective locus suggest potential new protective mechanisms for AD development.
Abstract INTRODUCTION Despite a two‐fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. METHODS Genome‐wide association studies (GWAS) ...of 2,903 AD cases and 6,265 controls of African ancestry. Within‐dataset results were meta‐analyzed, followed by functional genomics analyses. RESULTS A novel AD‐risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, P = 3.68×10 −9 ). Two additional novel common and nine rare loci were identified with suggestive associations ( P < 9×10 −7 ). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 ( ASCL1 ), suggesting that this association is modulated by regional origin of local African ancestry. DISCUSSION These analyses identified novel AD‐associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. Highlights Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta‐analysis identified a novel genome‐wide significant AD‐risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome‐wide significance at P < 9×10−7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry‐informed genetic screening tools and therapeutic interventions.
Background
Strong associations between ApoE ε4 and Alzheimer disease (AD) risk have been confirmed worldwide, but there is variability in the effect size across populations. African (AF)‐descent ...populations have a lower risk from ApoE ε4 compared to other populations. Studies in admixed populations showed that the AF ancestral background surrounding the ApoE gene reduces the ε4 risk allele effect. Our aim in this study is to identify genetic loci that show a protective effect in AF ancestral background.
Method
Primary analyses included imputed data from 6,417 African American (AA) individuals (Kunkle et al. 2020). We estimated global ancestry using a PC‐AiR approach that is robust to known and cryptic relatedness. To identify any protective factors interacting with ApoE in the AF local ancestry region, we performed association analyses using a logistic regression model with ApoE ε4 allele as an interaction term and adjusted for genome‐wide ancestry, age, and sex. We performed replication analysis using Whole Genome Sequence (WGS) data on 837 African LA ancestry individuals from Ibadan/Nigeria.
Result
We identified a locus (rs10423769) that lies within a large cluster of pregnancy specific beta‐1 glycoproteins on chromosome 19, ∼ 2 mB from ApoE, with a significant interaction with the ApoE ε4 allele (β=‐0.53; SE=0.12;p‐value=1.2x10‐5; FDR adjusted p‐value<0.05) in the logistic regression model in the imputed AA samples. We replicated the association in the Nigerian population (β=‐1.35; SE=0.52;p‐value=9.6x10‐3). The epistatic interaction reduced the ApoE ε4 allele risk in AD individuals.
Conclusion
This study identifies a new locus that reduces the risk effect of ApoE ε4 in AD in AF. rs10423769 is a common allele in AF‐descent populations (minor allele frequency (MAF) = 0.12), rare in Europeans (MAF = 0.003) and monomorphic in East Asians. Our results confirm that the AF ancestral background surrounding the ApoE gene harbors protective factors that help mitigate the effect of the detrimental ε4 allele.
To compare the effect of obesity and related risk factors on 10-year mortality in two cohorts of older adults of African descent; one from the United States and one from Nigeria.
Study participants ...were community residents aged 70 or older of African descent living in Indianapolis, Indiana (N = 1,269) or Ibadan, Nigeria (1,197). We compared survival curves between the two cohorts by obesity class and estimated the effect of obesity class on mortality in Cox proportional hazards models controlling for age, gender, alcohol use, and smoking history, and the cardiometabolic biomarkers blood pressure, triglycerides, high-density lipoprotein, low-density lipoprotein, and C-reactive protein.
We found that underweight was associated with an increased risk of death in both the Yoruba (hazards ratio = 1.35, 95% confidence interval: 1.12-1.63) and African American samples (hazards ratio = 2.49, 95% confidence interval: 1.40-4.43) compared with those with normal weight. The overweight and obese participants in both cohorts experienced survival similar to the normal weight participants. Controlling for cardiometabolic biomarkers had little effect on the obesity-specific hazard ratios in either cohort.
Despite significant differences across these two cohorts in terms of obesity and biomarker levels, overall 10-year survival and obesity class-specific survival were remarkably similar.
Background Panic disorder is a common chronic illness that is often unrecognized, misdiagnosed, and untreated because it often presents to the physicians with symptoms that are similar to those of ...emergency medical conditions. One study of the prevalence of panic disorder in the general population in Nigeria has been published, but no studies have examined the prevalence of panic disorder in a sample of Nigerian patients with cardiac symptoms. This study investigated the 12-month prevalence of panic disorder among patients who were referred for an electrocardiogram in a Nigerian teaching hospital. Methods Three hundred consecutive patients who were referred for an electrocardiogram were assessed for panic disorder using the Structured Clinical Interview for DSM-IV (SCID). Results The prevalence of panic attacks and panic disorder were 10.0% and 7.0%, respectively. Age was associated with the presence of both panic attacks and panic disorder. Conclusions This study suggests that panic disorder is common among patients who are referred for an electrocardiogram. It is recommended that patients whose cardiovascular or respiratory symptoms are not well explained by the diseases of such systems be evaluated for mental illness.
CONTEXT Alzheimer disease (AD) represents a major and increasing public health
problem. If populations were identified with significantly lower or higher
incidence rates of AD, the search for risk ...factors in the genesis of AD could
be greatly enhanced. OBJECTIVE To compare incidence rates of dementia and AD in 2 diverse, elderly
community-dwelling populations. DESIGN The Indianapolis-Ibadan Dementia Project, a longitudinal, prospective
population-based study consisting of a baseline survey (1992-1993) and 2 subsequent
follow-up waves after 2 years (1994-1995) and 5 years (1997-1998). Each wave
followed a 2-stage design, with an in-home screening interview followed by
a full diagnostic workup of a subsample of participants based on screening
performance. SETTING AND PARTICIPANTS A total of 2459 community-dwelling Yoruba residents of Ibadan, Nigeria,
without dementia, and 2147 community-dwelling African American residents of
Indianapolis, Ind, without dementia (all aged 65 years or older). The cohorts
were followed up for a mean of 5.1 years and 4.7 years, respectively. MAIN OUTCOME MEASURES Incident cases of dementia and AD in each of the 2 populations. RESULTS The age-standardized annual incidence rates were significantly lower
among Yoruba than among African Americans for dementia (Yoruba, 1.35% 95%
confidence interval {CI}, 1.13%-1.56%; African Americans, 3.24% 95% CI,
2.11%-4.38%) and for AD (Yoruba, 1.15% 95% CI, 0.96%-1.35%; African Americans,
2.52% 95% CI, 1.40%-3.64%). CONCLUSION This is the first report of incidence rate differences for dementia
and AD in studies of 2 populations from nonindustrialized and industrialized
countries using identical methods and the same group of investigators in both
sites. Further explorations of these population differences may identify potentially
modifiable environmental or genetic factors to account for site differences
in dementia and AD.
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