Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation
Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2019-02-01
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| Series: | Platelets |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/09537104.2017.1384538 |
| _version_ | 1797684264885551104 |
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| author | Ming-Huei Chen Lisa R. Yanek Joshua D. Backman John D. Eicher Jennifer E. Huffman Yoav Ben-Shlomo Andrew D. Beswick Laura M. Yerges-Armstrong Alan R. Shuldiner Jeffrey R. O’Connell Rasika A. Mathias Diane M. Becker Lewis C. Becker Joshua P. Lewis Andrew D. Johnson Nauder Faraday |
| author_facet | Ming-Huei Chen Lisa R. Yanek Joshua D. Backman John D. Eicher Jennifer E. Huffman Yoav Ben-Shlomo Andrew D. Beswick Laura M. Yerges-Armstrong Alan R. Shuldiner Jeffrey R. O’Connell Rasika A. Mathias Diane M. Becker Lewis C. Becker Joshua P. Lewis Andrew D. Johnson Nauder Faraday |
| author_sort | Ming-Huei Chen |
| collection | DOAJ |
| description | Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10–7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20–50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study. |
| first_indexed | 2024-03-12T00:27:02Z |
| format | Article |
| id | doaj.art-5aa226b92c0744349f37efaa641d1094 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:27:02Z |
| publishDate | 2019-02-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-5aa226b92c0744349f37efaa641d10942023-09-15T10:31:58ZengTaylor & Francis GroupPlatelets0953-71041369-16352019-02-0130216417310.1080/09537104.2017.13845381384538Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregationMing-Huei Chen0Lisa R. Yanek1Joshua D. Backman2John D. Eicher3Jennifer E. Huffman4Yoav Ben-Shlomo5Andrew D. Beswick6Laura M. Yerges-Armstrong7Alan R. Shuldiner8Jeffrey R. O’Connell9Rasika A. Mathias10Diane M. Becker11Lewis C. Becker12Joshua P. Lewis13Andrew D. Johnson14Nauder Faraday15National Heart, Lung and Blood InstituteJohns Hopkins University School of MedicineUniversity of Maryland School of MedicineNational Heart, Lung and Blood InstituteNational Heart, Lung and Blood InstituteUniversity of BristolUniversity of BristolUniversity of Maryland School of MedicineUniversity of Maryland School of MedicineUniversity of Maryland School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineJohns Hopkins University School of MedicineUniversity of Maryland School of MedicineNational Heart, Lung and Blood InstituteJohns Hopkins University School of MedicinePrevious genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10–7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20–50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.http://dx.doi.org/10.1080/09537104.2017.1384538plateletsplatelet aggregationsnpgenetic associationexomeplatelet reactivity |
| spellingShingle | Ming-Huei Chen Lisa R. Yanek Joshua D. Backman John D. Eicher Jennifer E. Huffman Yoav Ben-Shlomo Andrew D. Beswick Laura M. Yerges-Armstrong Alan R. Shuldiner Jeffrey R. O’Connell Rasika A. Mathias Diane M. Becker Lewis C. Becker Joshua P. Lewis Andrew D. Johnson Nauder Faraday Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation Platelets platelets platelet aggregation snp genetic association exome platelet reactivity |
| title | Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation |
| title_full | Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation |
| title_fullStr | Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation |
| title_full_unstemmed | Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation |
| title_short | Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation |
| title_sort | exome chip meta analysis identifies association between variation in ankrd26 and platelet aggregation |
| topic | platelets platelet aggregation snp genetic association exome platelet reactivity |
| url | http://dx.doi.org/10.1080/09537104.2017.1384538 |
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