Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences.
Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-09-01
|
| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1009019 |
| _version_ | 1819364846835073024 |
|---|---|
| author | Cassandra N Spracklen Apoorva K Iyengar Swarooparani Vadlamudi Chelsea K Raulerson Anne U Jackson Sarah M Brotman Ying Wu Maren E Cannon James P Davis Aaron T Crain Kevin W Currin Hannah J Perrin Narisu Narisu Heather M Stringham Christian Fuchsberger Adam E Locke Ryan P Welch Johanna K Kuusisto Päivi Pajukanta Laura J Scott Yun Li Francis S Collins Michael Boehnke Markku Laakso Karen L Mohlke |
| author_facet | Cassandra N Spracklen Apoorva K Iyengar Swarooparani Vadlamudi Chelsea K Raulerson Anne U Jackson Sarah M Brotman Ying Wu Maren E Cannon James P Davis Aaron T Crain Kevin W Currin Hannah J Perrin Narisu Narisu Heather M Stringham Christian Fuchsberger Adam E Locke Ryan P Welch Johanna K Kuusisto Päivi Pajukanta Laura J Scott Yun Li Francis S Collins Michael Boehnke Markku Laakso Karen L Mohlke |
| author_sort | Cassandra N Spracklen |
| collection | DOAJ |
| description | Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms. |
| first_indexed | 2024-12-24T23:05:26Z |
| format | Article |
| id | doaj.art-e4c6efa9e7de430ca829bd7499f7efca |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-24T23:05:26Z |
| publishDate | 2020-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-e4c6efa9e7de430ca829bd7499f7efca2022-12-21T16:35:02ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-09-01169e100901910.1371/journal.pgen.1009019Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences.Cassandra N SpracklenApoorva K IyengarSwarooparani VadlamudiChelsea K RaulersonAnne U JacksonSarah M BrotmanYing WuMaren E CannonJames P DavisAaron T CrainKevin W CurrinHannah J PerrinNarisu NarisuHeather M StringhamChristian FuchsbergerAdam E LockeRyan P WelchJohanna K KuusistoPäivi PajukantaLaura J ScottYun LiFrancis S CollinsMichael BoehnkeMarkku LaaksoKaren L MohlkeLoci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.https://doi.org/10.1371/journal.pgen.1009019 |
| spellingShingle | Cassandra N Spracklen Apoorva K Iyengar Swarooparani Vadlamudi Chelsea K Raulerson Anne U Jackson Sarah M Brotman Ying Wu Maren E Cannon James P Davis Aaron T Crain Kevin W Currin Hannah J Perrin Narisu Narisu Heather M Stringham Christian Fuchsberger Adam E Locke Ryan P Welch Johanna K Kuusisto Päivi Pajukanta Laura J Scott Yun Li Francis S Collins Michael Boehnke Markku Laakso Karen L Mohlke Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. PLoS Genetics |
| title | Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. |
| title_full | Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. |
| title_fullStr | Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. |
| title_full_unstemmed | Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. |
| title_short | Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. |
| title_sort | adiponectin gwas loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences |
| url | https://doi.org/10.1371/journal.pgen.1009019 |
| work_keys_str_mv | AT cassandranspracklen adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT apoorvakiyengar adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT swarooparanivadlamudi adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT chelseakraulerson adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT anneujackson adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT sarahmbrotman adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT yingwu adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT marenecannon adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT jamespdavis adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT aarontcrain adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT kevinwcurrin adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT hannahjperrin adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT narisunarisu adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT heathermstringham adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT christianfuchsberger adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT adamelocke adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT ryanpwelch adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT johannakkuusisto adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT paivipajukanta adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT laurajscott adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT yunli adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT francisscollins adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT michaelboehnke adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT markkulaakso adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences AT karenlmohlke adiponectingwaslociharboringextensiveallelicheterogeneityexhibitdistinctmolecularconsequences |