Dataset Information

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

ABSTRACT: IMPORTANCE:Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE:To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS:Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES:The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS:The African American cohort had a low degree of inbreeding (F?~?0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P?=?.004) or greater than 3 Mb (P?=?.02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2?=?.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2?=?.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2?=?.03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs?>1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs?>2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs?>3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2?=?.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2?=?.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE:To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

SUBMITTER: Ghani M

PROVIDER: S-EPMC4641052 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

Ghani Mahdi M Reitz Christiane C Cheng Rong R Vardarajan Badri Narayan BN Jun Gyungah G Sato Christine C Naj Adam A Rajbhandary Ruchita R Wang Li-San LS Valladares Otto O Lin Chiao-Feng CF Larson Eric B EB Graff-Radford Neill R NR Evans Denis D De Jager Philip L PL Crane Paul K PK Buxbaum Joseph D JD Murrell Jill R JR Raj Towfique T Ertekin-Taner Nilufer N Logue Mark M Baldwin Clinton T CT Green Robert C RC Barnes Lisa L LL Cantwell Laura B LB Fallin M Daniele MD Go Rodney C P RC Griffith Patrick A PA Obisesan Thomas O TO Manly Jennifer J JJ Lunetta Kathryn L KL Kamboh M Ilyas MI Lopez Oscar L OL Bennett David A DA Hendrie Hugh H Hall Kathleen S KS Goate Alison M AM Byrd Goldie S GS Kukull Walter A WA Foroud Tatiana M TM Haines Jonathan L JL Farrer Lindsay A LA Pericak-Vance Margaret A MA Lee Joseph H JH Schellenberg Gerard D GD St George-Hyslop Peter P Mayeux Richard R Rogaeva Ekaterina E

JAMA neurology 20151101 11

<h4>Importance</h4>Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.<h4>Objective</h4>To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.<h4> ...[more]

PMID: 26366463

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Project description:Background Alpaca (Vicugna pacos), llama (Lama glama), vicugna (Vicugna vicugna) and guanaco (Lama guanicoe), are the camelid species distributed over the Andean high-altitude grasslands, the Altiplano, and the Patagonian arid steppes. Despite the wide interest on these animals, most of the loci under selection are still unknown. Using whole-genome sequencing (WGS) data we investigated the occurrence and the distribution of Runs Of Homozygosity (ROHs) across the South American Camelids (SACs) genome to identify the genetic relationship between the four species and the potential signatures of selection. Results A total of 37 WGS samples covering the four species was included in the final analysis. The multi-dimensional scaling approach showed a clear separation between the four species; however, admixture analysis suggested a strong genetic introgression from vicugna and llama to alpaca. Conversely, very low genetic admixture of the guanaco with the other SACs was found. The four species did not show significant differences in the number, length of ROHs (100-500 kb) and genomic inbreeding values. Longer ROHs (> 500 kb) were found almost exclusively in alpaca. Seven overlapping ROHs were shared by alpacas, encompassing nine loci (FGF5, LOC107034918, PRDM8, ANTXR2, LOC102534792, BSN, LOC116284892, DAG1 and RIC8B) while nine overlapping ROHs were found in llama with twenty-five loci annotated (ERC2, FZD9, BAZ1B, BCL7B, LOC116284208, TBL2, MLXIPL, PHF20, TRNAD-AUC, LOC116284365, RBM39, ARFGEF2, DCAF5, EXD2, HSPB11, LRRC42, LDLRAD1, TMEM59, LOC107033213, TCEANC2, LOC102545169, LOC116278408, SMIM15, NDUFAF2 and RCOR1). Four overlapping ROHs, with three annotated loci (DLG1, KAT6B and PDE4D) and three overlapping ROHs, with seven annotated genes (ATP6V1E1, BCL2L13, LOC116276952, BID, KAT6B, LOC116282667 and LOC107034552), were detected for vicugna and guanaco, respectively. Conclusions The signatures of selection revealed genomic areas potentially selected for production traits as well as for natural adaptation to harsh environment. Alpaca and llama hint a selection driven by environment as well as by farming purpose while vicugna and guanaco showed selection signals for adaptation to harsh environment. Interesting, signatures of selection on KAT6B gene were identified for both vicugna and guanaco, suggesting a positive effect on wild populations fitness. Such information may be of interest to further ecological and animal production studies. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-023-09547-3.

Project description:ImportanceCompared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.ObjectiveTo identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.Design, setting, and participantsThis genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.Main outcomes and measuresDiagnosis of Alzheimer disease.ResultsA total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.Conclusions and relevanceWhile the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Project description:IMPORTANCE The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding. OBJECTIVE To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations. DESIGN We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses. SETTING A whole-genome case-control ROH study. PARTICIPANTS A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants. EXPOSURE Alzheimer disease risk genes. MAIN OUTCOMES AND MEASURES We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection. RESULTS In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P = .0039), and this association was stronger with familial AD (P = .0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls). CONCLUSIONS AND RELEVANCE Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs.

Project description:ImportanceLittle is known regarding health outcomes associated with higher blood pressure (BP) levels measured outside the clinic among African American individuals.ObjectiveTo examine whether daytime and nighttime BP levels measured outside the clinic among African American individuals are associated with cardiovascular disease (CVD) and all-cause mortality independent of BP levels measured inside the clinic.Design, setting, and participantsThis prospective cohort study analyzed data from 1034 African American participants in the Jackson Heart Study who completed ambulatory BP monitoring at baseline (September 26, 2000, to March 31, 2004). Mean daytime and nighttime BPs were calculated based on measurements taken while participants were awake and asleep, respectively. Data were analyzed from July 1, 2017, to April 30, 2019.Main outcomes and measuresCardiovascular disease events, including coronary heart disease and stroke, experienced through December 31, 2014, and all-cause mortality experienced through December 31, 2016, were adjudicated. The associations of daytime BP and nighttime BP, separately, with CVD events and all-cause mortality were determined using Cox proportional hazards regression models.ResultsA total of 1034 participants (mean [SD] age, 58.9 [10.9] years; 337 [32.6%] male; and 583 [56.4%] taking antihypertensive medication) were included in the study. The mean daytime systolic BP (SBP)/diastolic BP (DBP) was 129.4/77.6 mm Hg, and the mean nighttime SBP/DBP was 121.3/68.4 mm Hg. During follow-up (median [interquartile range], 12.5 [11.1-13.6] years for CVD and 14.8 [13.7-15.6] years for all-cause mortality), 113 CVD events and 194 deaths occurred. After multivariable adjustment, including in-clinic SBP and DBP, the hazard ratios (HRs) for CVD events for each SD higher level were 1.53 (95% CI, 1.24-1.88) for daytime SBP (per 13.5 mm Hg), 1.48 (95% CI, 1.22-1.80) for nighttime SBP (per 15.5 mm Hg), 1.25 (95% CI, 1.02-1.51) for daytime DBP (per 9.3 mm Hg), and 1.30 (95% CI, 1.06-1.59) for nighttime DBP (per 9.5 mm Hg). Nighttime SBP was associated with all-cause mortality (HR per 1-SD higher level, 1.24; 95% CI, 1.06-1.45), but no association was present for daytime SBP (HR, 1.13; 95% CI, 0.97-1.33) and daytime (HR, 0.95; 95% CI, 0.81-1.10) and nighttime (HR, 1.06; 95% CI, 0.90-1.24) DBP.Conclusions and relevanceAmong African American individuals, higher daytime and nighttime SBPs were associated with an increased risk for CVD events and all-cause mortality independent of BP levels measured in the clinic. Measurement of daytime and nighttime BP using ambulatory monitoring during a 24-hour period may help identify African American individuals who have an increased cardiovascular disease risk.

Dataset Information

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

Publications

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

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