Interactions within the MHC contribute to the genetic architecture of celiac disease.
Interaction analysis of GWAS can detect signal that would be ignored by single variant analysis, yet few robust interactions in humans have been detected. Recent work has highlighted interactions in the MHC region between known HLA risk haplotypes for various autoimmune diseases. To better understan...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5345796?pdf=render |
| _version_ | 1818927511818469376 |
|---|---|
| author | Benjamin Goudey Gad Abraham Eder Kikianty Qiao Wang Dave Rawlinson Fan Shi Izhak Haviv Linda Stern Adam Kowalczyk Michael Inouye |
| author_facet | Benjamin Goudey Gad Abraham Eder Kikianty Qiao Wang Dave Rawlinson Fan Shi Izhak Haviv Linda Stern Adam Kowalczyk Michael Inouye |
| author_sort | Benjamin Goudey |
| collection | DOAJ |
| description | Interaction analysis of GWAS can detect signal that would be ignored by single variant analysis, yet few robust interactions in humans have been detected. Recent work has highlighted interactions in the MHC region between known HLA risk haplotypes for various autoimmune diseases. To better understand the genetic interactions underlying celiac disease (CD), we have conducted exhaustive genome-wide scans for pairwise interactions in five independent CD case-control studies, using a rapid model-free approach to examine over 500 billion SNP pairs in total. We found 14 independent interaction signals within the MHC region that achieved stringent replication criteria across multiple studies and were independent of known CD risk HLA haplotypes. The strongest independent CD interaction signal corresponded to genes in the HLA class III region, in particular PRRC2A and GPANK1/C6orf47, which are known to contain variants for non-Hodgkin's lymphoma and early menopause, co-morbidities of celiac disease. Replicable evidence for statistical interaction outside the MHC was not observed. Both within and between European populations, we observed striking consistency of two-locus models and model distribution. Within the UK population, models of CD based on both interactions and additive single-SNP effects increased explained CD variance by approximately 1% over those of single SNPs. The interactions signal detected across the five cohorts indicates the presence of novel associations in the MHC region that cannot be detected using additive models. Our findings have implications for the determination of genetic architecture and, by extension, the use of human genetics for validation of therapeutic targets. |
| first_indexed | 2024-12-20T03:14:11Z |
| format | Article |
| id | doaj.art-6ab291aa82014ab7827db4724185604e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T03:14:11Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6ab291aa82014ab7827db4724185604e2022-12-21T19:55:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01123e017282610.1371/journal.pone.0172826Interactions within the MHC contribute to the genetic architecture of celiac disease.Benjamin GoudeyGad AbrahamEder KikiantyQiao WangDave RawlinsonFan ShiIzhak HavivLinda SternAdam KowalczykMichael InouyeInteraction analysis of GWAS can detect signal that would be ignored by single variant analysis, yet few robust interactions in humans have been detected. Recent work has highlighted interactions in the MHC region between known HLA risk haplotypes for various autoimmune diseases. To better understand the genetic interactions underlying celiac disease (CD), we have conducted exhaustive genome-wide scans for pairwise interactions in five independent CD case-control studies, using a rapid model-free approach to examine over 500 billion SNP pairs in total. We found 14 independent interaction signals within the MHC region that achieved stringent replication criteria across multiple studies and were independent of known CD risk HLA haplotypes. The strongest independent CD interaction signal corresponded to genes in the HLA class III region, in particular PRRC2A and GPANK1/C6orf47, which are known to contain variants for non-Hodgkin's lymphoma and early menopause, co-morbidities of celiac disease. Replicable evidence for statistical interaction outside the MHC was not observed. Both within and between European populations, we observed striking consistency of two-locus models and model distribution. Within the UK population, models of CD based on both interactions and additive single-SNP effects increased explained CD variance by approximately 1% over those of single SNPs. The interactions signal detected across the five cohorts indicates the presence of novel associations in the MHC region that cannot be detected using additive models. Our findings have implications for the determination of genetic architecture and, by extension, the use of human genetics for validation of therapeutic targets.http://europepmc.org/articles/PMC5345796?pdf=render |
| spellingShingle | Benjamin Goudey Gad Abraham Eder Kikianty Qiao Wang Dave Rawlinson Fan Shi Izhak Haviv Linda Stern Adam Kowalczyk Michael Inouye Interactions within the MHC contribute to the genetic architecture of celiac disease. PLoS ONE |
| title | Interactions within the MHC contribute to the genetic architecture of celiac disease. |
| title_full | Interactions within the MHC contribute to the genetic architecture of celiac disease. |
| title_fullStr | Interactions within the MHC contribute to the genetic architecture of celiac disease. |
| title_full_unstemmed | Interactions within the MHC contribute to the genetic architecture of celiac disease. |
| title_short | Interactions within the MHC contribute to the genetic architecture of celiac disease. |
| title_sort | interactions within the mhc contribute to the genetic architecture of celiac disease |
| url | http://europepmc.org/articles/PMC5345796?pdf=render |
| work_keys_str_mv | AT benjamingoudey interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT gadabraham interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT ederkikianty interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT qiaowang interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT daverawlinson interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT fanshi interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT izhakhaviv interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT lindastern interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT adamkowalczyk interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease AT michaelinouye interactionswithinthemhccontributetothegeneticarchitectureofceliacdisease |