scholarly journals Fine-Mapping Array Design for Multi-Ethnic Studies of Multiple Sclerosis

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 903
Author(s):  
Ashley H. Beecham ◽  
Jacob L. McCauley
Keyword(s):  
Multiple Sclerosis ◽  
African American ◽  
Fine Mapping ◽  
Genetic Associations ◽  
Genotyping Array ◽  
Locus Heterogeneity ◽  
Base Content ◽  
Risk Variants ◽  
Mapping Array ◽  
Causal Variants

While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge gained from replication efforts in Hispanic and African American populations can be utilized to more efficiently fine-map these risk loci. To this end, we have customized a genotyping array by adding ~20,000 bead types (~17,000 variants) to the base content of the Ilumina Infinium expanded multi-ethnic genotyping array and the Infinium ImmunoArray-24 v2 BeadChip. These custom bead types were chosen to allow for the detection of causal variation (1) in the presence of allelic and locus heterogeneity, by incorporating regulatory and coding variation within 1-Mb of previously identified risk variants and (2) in the absence of allelic and locus heterogeneity by incorporation of variants using linkage disequilibrium criteria, which are based on knowledge of replication status in Hispanic and African American study samples. This array has been designed to maximize fine-mapping potential for currently identified MS susceptibility loci, particularly in multi-ethnic populations. The strategies described here could be additionally informative for fine-mapping of other disease phenotypes.

scholarly journals Genetic associations at regulatory phenotypes improve fine-mapping of causal variants for twelve immune-mediated diseases

2020 ◽  
Author(s):  
Kousik Kundu ◽  
Alice L. Mann ◽  
Manuel Tardaguila ◽  
Stephen Watt ◽  
Hannes Ponstingl ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Meta Analysis ◽  
Cell Types ◽  
Genetic Associations ◽  
Sequencing Data ◽  
Immune Mediated ◽  
Causal Genes ◽  
Causal Variants

AbstractThe identification of causal genetic variants for common diseases improves understanding of disease biology. Here we use data from the BLUEPRINT project to identify regulatory quantitative trait loci (QTL) for three primary human immune cell types and use these to fine-map putative causal variants for twelve immune-mediated diseases. We identify 340 unique, non major histocompatibility complex (MHC) disease loci that colocalise with high (>98%) posterior probability with regulatory QTLs, and apply Bayesian frameworks to fine-map associations at each locus. We show that fine-mapping applied to regulatory QTLs yields smaller credible set sizes and higher posterior probabilities for candidate causal variants compared to disease summary statistics. We also describe a systematic under-representation of insertion/deletion (INDEL) polymorphisms in credible sets derived from publicly available disease meta-analysis when compared to QTLs based on genome-sequencing data. Overall, our findings suggest that fine-mapping applied to disease-colocalising regulatory QTLs can enhance the discovery of putative causal disease variants and provide insights into the underlying causal genes and molecular mechanisms.

scholarly journals Genetic susceptibility to multiple sclerosis in African Americans

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0254945
Author(s):  
Douglas S. Goodin ◽  
Jorge R. Oksenberg ◽  
Venceslas Douillard ◽  
Pierre-Antoine Gourraud ◽  
Nicolas Vince
Keyword(s):  
Multiple Sclerosis ◽  
African American ◽  
African Americans ◽  
Genetic Susceptibility ◽  
Reference Group ◽  
Single Copy ◽  
Class Ii ◽  
Control Group ◽  
Source Population ◽  
Genetic Associations

Objective To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans. Background Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort. Design/methods The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational “Be the Match” registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms. Results Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)–similar to that observed in the WTCCC (OR = 3.25; p<10−168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)–again, similar to the WTCCC (OR = 2.2; p<10−38). Moreover, four African haplotypes were “protective” relative to a neutral reference, to three European CEHs, and also to the five other African CEHs. Conclusions The common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were “protective”–perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.

scholarly journals Fine-mapping genetic associations

2020 ◽  
Vol 29 (R1) ◽  
pp. R81-R88 ◽  
Author(s):  
Anna Hutchinson ◽  
Jennifer Asimit ◽  
Chris Wallace
Keyword(s):  
Linkage Disequilibrium ◽  
Fine Mapping ◽  
Genetic Variants ◽  
Functional Annotation ◽  
Causal Variant ◽  
Genetic Associations ◽  
Multiple Datasets ◽  
Annotation Data ◽  
Causal Variants ◽  
Summary Data

Abstract Whilst thousands of genetic variants have been associated with human traits, identifying the subset of those variants that are causal requires a further ‘fine-mapping’ step. We review the basic fine-mapping approach, which is computationally fast and requires only summary data, but depends on an assumption of a single causal variant per associated region which is recognized as biologically unrealistic. We discuss different ways that the approach has been built upon to accommodate multiple causal variants in a region and to incorporate additional layers of functional annotation data. We further review methods for simultaneous fine-mapping of multiple datasets, either exploiting different linkage disequilibrium (LD) structures across ancestries or borrowing information between distinct but related traits. Finally, we look to the future and the opportunities that will be offered by increasingly accurate maps of causal variants for a multitude of human traits.

scholarly journals CAUSALdb: a database for disease/trait causal variants identified using summary statistics of genome-wide association studies

2019 ◽  
Author(s):  
Jianhua Wang ◽  
Dandan Huang ◽  
Yao Zhou ◽  
Hongcheng Yao ◽  
Huanhuan Liu ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Genetic Variants ◽  
Association Studies ◽  
Complex Trait ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Genome Wide ◽  
Credible Sets ◽  
Causal Variants

Abstract Genome-wide association studies (GWASs) have revolutionized the field of complex trait genetics over the past decade, yet for most of the significant genotype-phenotype associations the true causal variants remain unknown. Identifying and interpreting how causal genetic variants confer disease susceptibility is still a big challenge. Herein we introduce a new database, CAUSALdb, to integrate the most comprehensive GWAS summary statistics to date and identify credible sets of potential causal variants using uniformly processed fine-mapping. The database has six major features: it (i) curates 3052 high-quality, fine-mappable GWAS summary statistics across five human super-populations and 2629 unique traits; (ii) estimates causal probabilities of all genetic variants in GWAS significant loci using three state-of-the-art fine-mapping tools; (iii) maps the reported traits to a powerful ontology MeSH, making it simple for users to browse studies on the trait tree; (iv) incorporates highly interactive Manhattan and LocusZoom-like plots to allow visualization of credible sets in a single web page more efficiently; (v) enables online comparison of causal relations on variant-, gene- and trait-levels among studies with different sample sizes or populations and (vi) offers comprehensive variant annotations by integrating massive base-wise and allele-specific functional annotations. CAUSALdb is freely available at http://mulinlab.org/causaldb.

Abstract 050: Fine-mapping and Bioinformatics Characterization of QT Interval Loci in African Americans: The Population Architecture Using Genomics and Epidemiology (PAGE) Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Christy L Avery ◽  
Praveen Sethupathy ◽  
Steven Buyske ◽  
Q. C He ◽  
Dan Y Lin ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Fine Mapping ◽  
Qt Interval ◽  
Functional Characterization ◽  
Regulatory Elements ◽  
European Ancestry ◽  
Functional Evaluation ◽  
Human Cardiomyocytes

The QT interval (QT) is a heritable trait and its prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Most genetic studies of QT have examined populations of European ancestry, although the increased genetic diversity in populations of African descent provides opportunity for fine-mapping, which can help narrow association signals and identify candidates for functional characterization. We examined whether eleven previously identified QT loci comprising 6,681 variants on the Illumina Metabochip array were associated with QT in 7,516 African American participants from the Atherosclerosis Risk in Communities study and Women’s Health Initiative clinical trial. Among associated loci, we used conditional analyses and queried bioinformatics databases to identify and functionally categorize signals. We identified nine of the eleven QT loci in African American populations ( P <0.0045 under an additive genetic model adjusting for ancestry and demographic characteristics: NOS1AP, ATP1B1, SCN5A, SLC35F1, KCNH2, KCNQ1, LITAF, NDRG4, and RFFL ). We also identified two independent secondary signals in NOS1AP and ATP1B1 ( P < 7.4x10 −6 ). Conditional analyses adjusting for published loci in European populations demonstrated that eight of these eleven SNPs (nine primary; two secondary) were independent of previously reported SNPs. We then performed the first bioinformatics-based functional characterization of QT loci using the eleven primary and secondary variants and SNPs in strong LD (r 2 > 0.5) among these African American participants. Only the SCN5A locus included a non-synonymous coding variant (rs1805124, H558R, r 2 = 0.7 with primary SNP rs9871385, P = 4.7x10 −4 ). The remaining ten loci harbored variants located exclusively within non-coding regions. Specifically, three contained SNPs within candidate long-range regulatory elements in human cardiomyocytes, five were in or near annotated promoter regions, and the remaining two were in un-annotated, but highly conserved non-coding elements. Several of the QT risk alleles at these SNPs significantly alter the predicted binding affinity for transcription factors, such as TBX5 and AhR, which have been previously implicated in cardiac formation and function. In summary, the findings provide compelling evidence that the same genes influence variation in QT across global populations and that additional, independent signals exist in African Americans. Moreover, of those SNPs identified as strong candidates for functional evaluation, the majority implicate gene regulatory dysfunction in QT prolongation.

scholarly journals Admixture mapping and fine-mapping of type 2 diabetes susceptibility loci in African American women

2018 ◽  
Vol 63 (11) ◽  
pp. 1109-1117 ◽  
Author(s):  
José M. Uribe-Salazar ◽  
Julie R. Palmer ◽  
Stephen A. Haddad ◽  
Lynn Rosenberg ◽  
Edward A. Ruiz-Narváez
Keyword(s):  
Type 2 Diabetes ◽  
African American ◽  
African American Women ◽  
Fine Mapping ◽  
Admixture Mapping ◽  
Susceptibility Loci ◽  
Diabetes Susceptibility ◽  
American Women

scholarly journals High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazutoyo Osoegawa ◽  
Lisa E. Creary ◽  
Gonzalo Montero-Martín ◽  
Kalyan C. Mallempati ◽  
Sridevi Gangavarapu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Statistical Significance ◽  
Hla Class I ◽  
Protective Effects ◽  
Genetic Associations ◽  
Hla Alleles ◽  
Hla Genes ◽  
Haplotype Allele ◽  
Family Based ◽  
Hla Haplotypes

Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p &lt; 2.20e-16; mTDT: p =1.61e-07; CC: p &lt; 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.

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