Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci

Abstract
Data availability
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Abstract

To uncover novel significant association signals (P<5x10^-8), GWAS requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5x10^-8 ≤ P < 5x10^-4) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and ESC-derived hypothalamic-like neurons. This approach, with its extremely low false positive rate, identified 15 loci at P<5x10^-5 in the 2010 GWAS, 13 of which achieved genome-wide significance by 2018, including at NAV1, MTIF3 and ADCY3. 80% of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing datasets without increasing sample size.

Data availability

Adipose ATAC-seq and promoter-focused capture C data is available in GEO under accession number GSE164912Hypothalamic Neuron ATAC-eq and promoter-focused capture C data is the subject of another atlas-based manuscript currently under peer review and through that process that dataset will be made available once the paper is published- the corresponding hypothalamus preprint can be found at: https://www.biorxiv.org/content/10.1101/2020.07.06.146951v1.full

The following data sets were generated

1. Hammond R
2. Pahl MC
3. Su C
4. Pippin JA
5. Wagley Y
6. Chesi A
7. Hankenson KD
8. Grant SF
(2021) Biological constraints on GWAS SNPs at suggestive significance thresholds reveal true BMI loci [hMSC_adipocytes_atacseq]
NCBI Gene Expression Omnibus, GSE164745.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE164745
1. Hammond R
2. Pahl MC
3. Su C
4. Pippin JA
5. Wagley Y
6. Chesi A
7. Hankenson KD
8. Grant SF
(2021) Biological constraints on GWAS SNPs at suggestive significance thresholds reveal true BMI loci [hMSC_adipocytes_captureC]
NCBI Gene Expression Omnibus, GSE164911.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE164911
1. Hammond RK
2. Pahl MC
3. Su C
4. Cousminer DL
5. Leonard ME
6. Lu S
7. Doege CA
8. Wagley Y
9. Hodge KM
10. Lasconi C
11. Johnson ME
12. Terry NA
13. Ghanem LR
14. Brown CS
15. Pippin JA
16. Hankenson KD
17. Leibel RL
18. Chesi A
19. Wells AD
20. Grant SFA
(2021) Biological constraints on GWAS SNPs at suggestive significance thresholds reveal true BMI loci
NCBI Gene Expression Omnibus, GSE164912.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE164912

The following previously published data sets were used

1. Speliotes EK
2. Willer
3. CJ
4. Berndt
5. SI
6. Monda
7. KL
8. Thorleifsson
9. G
10. Jackson
11. AU
12. Allen
13. HL
14. Lindgren
15. CM
16. Luan
17. J
18. Magi
19. R
20. et al
(2010) GWAS 2010 BMI Summary Statistics
GIANT consortium data files.

https://portals.broadinstitute.org/collaboration/giant/images/b/b7/GIANT_BMI_Speliotes2010_publicrelease_HapMapCeuFreq.txt.gz
1. Heid IM
2. Jackson AU
3. Randall JC
4. Winkler TW
5. Qi L
6. Steinthorsdottir V
7. Thorleifsson G
8. Zillikens MC
9. Speliotes EK
10. Magi R
11. et al
(2010) GWAS 2010 WHRadjBMI Summary Statistics
GIANT consortium data files.

https://portals.broadinstitute.org/collaboration/giant/images/8/87/GIANT_WHRadjBMI_Heid2010_publicrelease_HapMapCeuFreq.txt.gz
1. Locke AE
2. Kahali B
3. Berndt SI
4. Justice AE
5. Pers TH
6. Day FR
7. Powell C
8. Vedantam S
9. Buchkovich ML
10. Yang J
11. Croteau-Chonka DC
12. Esko T et al
(2015) GWAS 2015 BMI Summary Statistics
GIANT consortium data files.

https://portals.broadinstitute.org/collaboration/giant/images/1/15/SNP_gwas_mc_merge_nogc.tbl.uniq.gz
1. Shungin D
2. Winkler TW
3. Croteau-Chonka DC
4. Ferreira T
5. Locke AE
6. Magi R
7. Strawbridge R
8. Pers TH
9. Fischer K
10. Justice AE
11. Workalemahu T
12. Wu JM
13. et al
(2015) GWAS 2015 WHRadjBMI Summary Statistics
GIANT consortium data files.

https://portals.broadinstitute.org/collaboration/giant/images/e/eb/GIANT_2015_WHRadjBMI_COMBINED_EUR.txt.gz
1. Pulit SL
2. Stoneman C
3. Morris AP
4. Wood AR
5. Glastonbury CA
6. Tyrrell J
7. et al
(2018) GWAS 2018 BMI Summary Statistics
GIANT consortium data files.

https://portals.broadinstitute.org/collaboration/giant/images/c/c8/Meta-analysis_Locke_et_al%2BUKBiobank_2018_UPDATED.txt.gz
1. Yengo L
2. Sidorenko J
3. Kemper KE
4. Zheng Z
5. Wood AR
6. Weedon MN
7. Frayling TM
8. Hirschhorn J
9. Yang J
10. Visscher PM
11. GIANT Consortium
(2018) GWAS 2018 WHRadjBMI Summary Statistics
GIANT consortium data files.

https://zenodo.org/record/1251813/files/whradjbmi.giant-ukbb.meta-analysis.combined.23May2018.txt.gz

Article and author information

Author details

Reza K Hammond

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Matthew C Pahl

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Chun Su

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Diana L Cousminer

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Michelle E Leonard

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Sumei Lu

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Claudia A Doege

Division of Molecular Genetics (Pediatrics) and the Naomi Berrie Diabetes Center, Columbia University Vagelos College of Physicians and Surgeons, New York, United States

Competing interests
The authors declare that no competing interests exist.
Yadav Wagley

Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Kenyaita M Hodge

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Chiara Lasconi

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4684-704X
Matthew E Johnson

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
James A Pippin

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Kurt D Hankenson

Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Rudolph L Leibel

Division of Molecular Genetics (Pediatrics) and the Naomi Berrie Diabetes Center, Columbia University Vagelos College of Physicians and Surgeons, New York, United States

Competing interests
The authors declare that no competing interests exist.
Alessandra Chesi

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Andrew D Wells

Center for Spatial and Functional Genomics, Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Struan FA Grant

Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States

For correspondence
grants@email.chop.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2025-5302

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD056465)

Struan FA Grant

National Human Genome Research Institute (R01-HG010067)

Struan FA Grant

Children's Hospital of Philadelphia (Daniel B. Burke Endowed Chair for Diabetes Research)

Struan FA Grant

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.