Abstract
Background
Genome‐wide association studies (GWAS) are often from populations with European ancestry (EA). To test whether the variants identified from recent GWAS are associated with age of ...onset for AD in an African Americans and Africans, we performed associations studies using data from the Indianapolis‐Ibadan Dementia Project (IIDP).
Method
In this longitudinal study of two community dwelling cohorts of elderly African Americans and Nigerians, 1108 African Americans and 1184 Nigerians who were dementia free at enrollment and had GWAS data were included in the analysis. During follow‐up, 104 African American individuals and 79 Nigerians developed AD. Mean follow up time was 8.8 years for both samples. Biomarkers for cardiovascular disease including lipids, homocysteine, C‐reactive protein were also measured at the time of GWAS sample collection. Cox’s proportional hazard models were used to determine the associations between previously reported genetic variants (n = 23) and the age of onset for AD, after adjusting for age, sex, education and the number
APOE
ε4 allele. For variants replicated in the African American and Nigerian samples, ANCOVA models were used to examine the association between the variants and blood biomarker levels.
Result
In the African American sample, one variant (rs3752246) in the adenosine triphosphate‐binding cassette subfamily A member 7 (
ABCA7
) gene had a significant association with earlier AD onset (Hazard Ratio (HR) = 1.84, p = 0.0306). This
ABCA7
variant was not observed in the Nigerian sample. In the Nigerian sample, one variant (rs9331949) in the clusterin gene (
CLU
) and another variant (rs10498663) in the solute carrier family 24 member 4 gene (
SLC24A4
) were significantly associated with earlier onset of AD (rs9331949: HR = 2.05, p = 0.0069; rs10498663: HR = 1.55, p = 0.0401) while
APOE
was not significantly associated with age of onset for AD. In the Nigerian sample, rs10498663 in
SLC24A4
was significantly associated with higher levels of triglycerides (p = 0.0012).
Conclusion
We replicated rs3752246 in
ABCA7
for increased AD risk in African American participants in the IIDP study. In the Nigerian sample, the
CLU
and
SLC24A4
variants were associated with increased AD risk and have stronger associations with AD than
APOE
. Further research is needed to explore biological pathways underlying these associations.
Background
Genome‐wide association studies (GWAS) are often from populations with European ancestry (EA). To test whether the variants identified from recent GWAS are associated with age of onset for ...AD in an African Americans and Africans, we performed associations studies using data from the Indianapolis‐Ibadan Dementia Project (IIDP).
Method
In this longitudinal study of two community dwelling cohorts of elderly African Americans and Nigerians, 1108 African Americans and 1184 Nigerians who were dementia free at enrollment and had GWAS data were included in the analysis. During follow‐up, 104 African American individuals and 79 Nigerians developed AD. Mean follow up time was 8.8 years for both samples. Biomarkers for cardiovascular disease including lipids, homocysteine, C‐reactive protein were also measured at the time of GWAS sample collection. Cox’s proportional hazard models were used to determine the associations between previously reported genetic variants (n = 23) and the age of onset for AD, after adjusting for age, sex, education and the number APOE ε4 allele. For variants replicated in the African American and Nigerian samples, ANCOVA models were used to examine the association between the variants and blood biomarker levels.
Result
In the African American sample, one variant (rs3752246) in the adenosine triphosphate‐binding cassette subfamily A member 7 (ABCA7) gene had a significant association with earlier AD onset (Hazard Ratio (HR) = 1.84, p = 0.0306). This ABCA7 variant was not observed in the Nigerian sample. In the Nigerian sample, one variant (rs9331949) in the clusterin gene (CLU) and another variant (rs10498663) in the solute carrier family 24 member 4 gene (SLC24A4) were significantly associated with earlier onset of AD (rs9331949: HR = 2.05, p = 0.0069; rs10498663: HR = 1.55, p = 0.0401) while APOE was not significantly associated with age of onset for AD. In the Nigerian sample, rs10498663 in SLC24A4 was significantly associated with higher levels of triglycerides (p = 0.0012).
Conclusion
We replicated rs3752246 in ABCA7 for increased AD risk in African American participants in the IIDP study. In the Nigerian sample, the CLU and SLC24A4 variants were associated with increased AD risk and have stronger associations with AD than APOE. Further research is needed to explore biological pathways underlying these associations.
The frequency and predictors of post-stroke depression diagnosed according to codified criteria remain unknown in Nigeria.
We report on the predictors of post-stroke major depressive disorder (MDD) ...in Nigeria using standardized assessment methods.
Using a case-control design, we consecutively recruited 260 participants. Among them were 130 stroke survivors attending rehabilitation. Along with historical details, an exploration for MDD meeting criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders was carried out using a semi-structured interview. Cognition was assessed using both the Mini Mental State Examination and the modified Indiana University Token test, while disability was assessed using the modified Rankin Scale. Associations were explored using univariate and multivariate analyses.
The diagnosis of MDD was more frequently present in the stroke survivors (41.5%, p < 0.001). It was strongly associated with female gender (p < 0.001, O.R = 3.77, 95% C.I = 1.78-8.00), disability (p = 0.001, O.R = 3.27, 95% C.I = 1.57-6.83), and cognitive dysfunction (p < 0.001, O.R = 5.28, 95% C.I = 2.25-12.41). Female gender (p = 0.037, O.R = 2.65, 95% C.I = 1.06-6.62) and cognitive dysfunction (P = 0.03, O.R = 4.58, 95% C.I = 1.68-12.46) were independent predictors of post-stroke MDD.
Post stroke MDD is common in Nigerian survivors attending rehabilitation. The high rates reported in this population may be the result of factors affecting the efficient management of stroke in developing countries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background
Although African Americans are twice as likely to develop Alzheimer’s Disease (AD), individuals with African ancestry are under‐represented in genetic research of the disease. In the ...largest AD genome‐wide association studies to date for African‐Americans (Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified several novel susceptibility loci in addition to APOE, including ABCA7, API5, RBFOX1, and IGF1R.
Method
We performed a genome‐wide association meta‐analysis of 2,844 AD cases and 6,251 cognitively healthy controls of African ancestry (AA) assembled across 17 different cohorts. Single‐variant association analysis was conducted adjusting for age, sex, principal components, and subsequently APOE, applying logistic regression for case‐control and general estimating equations for family‐based datasets. Within‐study results were meta‐analyzed using METAL, and followed by gene‐based, pathway, scRNA‐seq, and colocalization analyses.
Result
Single variant meta‐analysis identified a novel genome‐wide significant AD risk locus in the MPDZ gene on chromosome 9p23 (rs141610415, MAF = .002, P = 3.68×10−9). MPDZ (MUPP1) is a vital component of the NMDAR signaling complex in excitatory synapses of hippocampal neurons critical for learning and memory. Two additional novel common loci and 9 novel rare loci approached genome‐wide significance at P<9×10−7. Genes at these loci are acting in biologically plausible pathways: signal transduction (PLEKHG1), synaptic transmission (CNTNAP4), synaptic connectivity (SDK1), neural development/function (SRGAP3, KIDINS220, UNC5C, TSSC1, TANC2), and neuronal differentiation (ASCL1). Single‐cell RNA‐sequence analysis shows that all genes are expressed in the brain, and that expression of the orthologs of SRGAP3, TANC2, and MMP16 is upregulated with amyloid toxicity in zebrafish. Pathway analyses support the notion that immune response, transcription/DNA repair, lipid processing, and intracellular trafficking are major AD‐associated pathways in African Americans. Except for SIPA1L2 and ACER3, all previously reported loci, including ABCA7, API5, RBFOX1 and IGF1R, remain genome‐wide or close to genome‐wide significant.
Conclusion
We identified several novel loci for AD in individuals with African ancestry with the strongest association observed for MPDZ involved in hippocampal synaptic signaling. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be critical to identify additional disease‐associated loci in individuals of African ancestry.
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African descent populations have a lower Alzheimer disease risk from ApoE epsilon4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European ...populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE epsilon4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE epsilon4 allele and the SNP rs10423769_A allele, (beta = -0.54,SE = 0.12,p-value = 7.50x10.sup.-6) in the discovery data set, and replicated this finding in Ibadan (beta = -1.32,SE = 0.52,p-value = 1.15x10.sup.-2) and Puerto Rican (beta = -1.27,SE = 0.64,p-value = 4.91x10.sup.-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (beta = -1.51,SE = 0.84,p-value = 7.26x10.sup.-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE epsilon4/epsilon4 carriers lacking the A allele to 2.1 for ApoE epsilon4/epsilon4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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 ...ε4 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 ε4 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 ε4 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 ε4 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 ε4 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.
Psychiatric disorders are common among people living with HIV in Nigeria. Adherence is necessary to optimise the outcome of antiretroviral therapy. In this study, we aimed to identify associations ...between antiretroviral adherence, measured by one-week and one-month self-reported missed doses, and psychiatric illness in a cohort previously assessed for psychiatric disorders using the Composite International Diagnostic Interview. The study participants comprised 151 adults with major depression, anxiety or suicidal symptoms, and 302 matched-control participants. Two controls were randomly selected for each case within the same gender and education level. We compared participants with psychiatric disorders (WPDs) and no psychiatric disorders (NPDs) on selected demographic and clinical variables, in addition to adherence. Participants with one or more missed doses in the preceding month had twice the odds of having a major depressive episode as those with no missed doses during this period (OR 2.22, 95% CI 1.03, 4.79). This association remained significant after adjusting for selected risk factors. There was no statistically significant difference between WPD and NPD groups on either one-week or one-month adherence, or on age, marital status, occupational class, HIV viral load at enrolment or current CD4 cell count. Among Nigerian adults with HIV, suboptimal antiretroviral adherence is associated with, and could be a sign of, depression. Routine self-report adherence assessments may potentially be utilised in identifying individuals at risk among this population.
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.
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