Multiple causal variants underlie genetic associations in humans
| العنوان: | Multiple causal variants underlie genetic associations in humans |
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| المؤلفون: | Nathan S. Abell, Stephen B. Montgomery, Emily Greenwald, Kevin S. Smith, Michael J. Gloudemans, Marianne K. DeGorter, Zihuai S He |
| المصدر: | Science. 375:1247-1254 |
| بيانات النشر: | American Association for the Advancement of Science (AAAS), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Linkage disequilibrium, Multifactorial Inheritance, Multiple Sclerosis, Quantitative Trait Loci, Disease, Quantitative trait locus, Biology, Linkage Disequilibrium, Untranslated Regions, Genetic variation, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetics, Multidisciplinary, Genome, Human, Platelet Count, Genetic Variation, Inflammatory Bowel Diseases, Asthma, Chromatin, Histone Code, Phenotype, Haplotypes, Expression quantitative trait loci, Trait, Genome-Wide Association Study, Transcription Factors |
| الوصف: | The majority of associations between genetic variation and human traits and diseases are non-coding and in strong linkage disequilibrium (LD) with surrounding genetic variation. In these cases, a single causal variant is often assumed to underlie the association, however no systematic assessment of the number of causal variants has been performed. In this study, we applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs, representing 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTL) and assessed each for colocalization across 114 traits. We identified 8,502 allele-independent regulatory regions containing 1,264 allele-specific regulatory variants, and found that 17.7% of eQTL contained more than one significant allelic effect. We show that detected regulatory variants are highly and specifically enriched for activating chromatin structures and allelic transcription factor binding, for which ETS-domain family members are a large driver. Integration of MPRA profiles with eQTL/complex trait colocalizations identified causal variant sets for associations with blood cell measurements, Asthma, Multiple Sclerosis, Inflammatory Bowel Disease, and Crohn’s Disease. These results demonstrate that a sizable number of association signals are manifest through multiple, tightly-linked causal variants requiring high-throughput functional assays for fine-mapping. |
| تدمد: | 1095-9203 0036-8075 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dea47c9160ac5082899a74ede8eda7ddTest https://doi.org/10.1126/science.abj5117Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....dea47c9160ac5082899a74ede8eda7dd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10959203 00368075 |
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