Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

/pdf/a-haplotype-map-of-the-human-genome-2oc85odzud.pdf

A haplotype map of the human genome

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

https://cdr.lib.unc.edu/downloads/xk81jn53s

A second generation human haplotype map of over 3.1 million SNPs

Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.

https://hal.archives-ouvertes.fr/hal-03378416/document

Global variation in copy number in the human genome

Missing Pieces in the NF-κB Puzzle

BackgroundAlpha globin gene (HBA) copy number is variable among people of African descent. HBA limits endothelial nitric oxide signaling and variation in gene copy number could modify kidney disease risk in this population. ObjectiveTo examine the association of HBA copy number with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We hypothesized that higher HBA copy number would be associated with greater CKD prevalence and ESKD incidence. DesignProspective, longitudinal cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study which enrolled participants from 2003 through 2007 and conducted follow-up through June 2014. Data were analyzed from January 2018 through January 2021. SettingCommunity-dwelling participants enrolled throughout the contiguous United States ParticipantsBlack Americans age 45 years and older MeasurementsHBA copy number was measured using droplet-digital PCR on genomic DNA; copy number ranged from 2 to [≥] 5 copies. The prevalence ratio (PR) of CKD and relative risk (RR) of incident reduced estimated glomerular filtration rate (eGFR) were calculated using modified Poisson multivariable regression employing a log-linear effect of HBA allele count. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. ResultsAmong 9,918 participants, HBA gene copy number frequencies were 4%, 28%, 67%, and 1% for 2, 3, 4, and [≥]5 copies, respectively. After adjusting for demographic, clinical, and genetic risk factors, each additional copy of HBA was associated with 14% greater prevalence of CKD (PR = 1.14, 95% CI 1.07 to 1.21; P < 0.0001). While there was no significant association with incident reduced eGFR (RR = 1.06, 95% CI 0.94 to 1.18; p = 0.36), the hazard of incident ESKD was 28% higher for each additional copy of HBA (HR = 1.28, 95% CI 1.01 to 1.61; P = 0.04). LimitationsThis study did not identify the mechanism by which HBA copy number modifies kidney disease risk. This study focused on Black Americans, a population with a high frequency of the 3.7 kb gene deletion; it is unknown whether HBA modifies kidney disease risk in other populations with the 3.7 kb deletion. ConclusionsIncreasing HBA copy number was associated with greater prevalent CKD and incident ESKD in a national longitudinal study of Black Americans. Funding SourceNational Institutes of Health

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HBA Copy Number and Kidney Disease Risk among Black Americans: a Longitudinal Cohort Study

Time-to-death is a potential confounder in observational studies of blood transfusion in severe malaria - Authors' reply.

Erratum: Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria (Human Genetics (2003) vol. 112 (379-386))

BACKGROUND: Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension. METHODS: Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure [≥] 140mmHg or diastolic blood pressure [≥] 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression. RESULTS: Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07). CONCLUSIONS: There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that genetic variation in alpha globin gene expression does not modify the risk of hypertension among Black American adults.

/pdf/alpha-globin-gene-copy-number-and-hypertension-risk-among-lln2d4a8.pdf

Hans Ackerman

Papers

HBA Copy Number and Kidney Disease Risk among Black Americans: a Longitudinal Cohort Study

Time-to-death is a potential confounder in observational studies of blood transfusion in severe malaria - Authors' reply.

Erratum: Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria (Human Genetics (2003) vol. 112 (379-386))

Alpha globin gene copy number and hypertension risk among Black Americans

Which Alpha Globin Gene Is Primarily Expressed in the Vascular Endothelium