Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

Sarah M. Brotman; Julia S. El-Sayed Moustafa; Li Guan; K. Alaine Broadaway; Dongmeng Wang; Anne U. Jackson; Ryan Welch; Kevin W. Currin; Max Tomlinson; Swarooparani Vadlamudi; Heather M. Stringham; Amy L. Roberts; Timo A. Lakka; Anniina Oravilahti; Lilian Fernandes Silva; Narisu Narisu; Michael R. Erdos; Tingfen Yan; Lori L. Bonnycastle; Chelsea K. Raulerson; Yasrab Raza; Xinyu Yan; Stephen C. J. Parker; Johanna Kuusisto; Päivi Pajukanta; Jaakko Tuomilehto; Francis S. Collins; Michael Boehnke; Michael I. Love; Heikki A. Koistinen; Markku Laakso; Karen L. Mohlke; Kerrin S. Small; Laura J. Scott

doi:10.1038/s41588-024-01982-6

Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

Sarah M. Brotman, Julia S. El-Sayed Moustafa, Li Guan, K. Alaine Broadaway, Dongmeng Wang, Anne U. Jackson, Ryan Welch, Kevin W. Currin, Max Tomlinson, Swarooparani Vadlamudi, Heather M. Stringham, Amy L. Roberts, Timo A. Lakka, Anniina Oravilahti, Lilian Fernandes Silva, Narisu Narisu, Michael R. Erdos, Tingfen Yan, Lori L. Bonnycastle, Chelsea K. RaulersonYasrab Raza, Xinyu Yan, Stephen C. J. Parker, Johanna Kuusisto, Päivi Pajukanta, Jaakko Tuomilehto, Francis S. Collins, Michael Boehnke, Michael I. Love, Heikki A. Koistinen, Markku Laakso, Karen L. Mohlke, Kerrin S. Small, Laura J. Scott

Twin Research & Genetic Epidemiology

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Abstract

Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS–eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS–eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

Original language	English
Article number	e1000888
Pages (from-to)	180-192
Number of pages	13
Journal	Nature Genetics
Volume	57
Issue number	1
Early online date	2 Jan 2025
DOIs	https://doi.org/10.1038/s41588-024-01982-6
Publication status	Published - Jan 2025

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Brotman, S. M., El-Sayed Moustafa, J. S., Guan, L., Broadaway, K. A., Wang, D., Jackson, A. U., Welch, R., Currin, K. W., Tomlinson, M., Vadlamudi, S., Stringham, H. M., Roberts, A. L., Lakka, T. A., Oravilahti, A., Fernandes Silva, L., Narisu, N., Erdos, M. R., Yan, T., Bonnycastle, L. L., ... Scott, L. J. (2025). Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits. Nature Genetics, 57(1), 180-192. Article e1000888. https://doi.org/10.1038/s41588-024-01982-6

@article{954168535fbd489f942d1b45d06dfc8f,

title = "Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.",

abstract = "Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS–eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS–eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.",

author = "Brotman, {Sarah M.} and {El-Sayed Moustafa}, {Julia S.} and Li Guan and Broadaway, {K. Alaine} and Dongmeng Wang and Jackson, {Anne U.} and Ryan Welch and Currin, {Kevin W.} and Max Tomlinson and Swarooparani Vadlamudi and Stringham, {Heather M.} and Roberts, {Amy L.} and Lakka, {Timo A.} and Anniina Oravilahti and {Fernandes Silva}, Lilian and Narisu Narisu and Erdos, {Michael R.} and Tingfen Yan and Bonnycastle, {Lori L.} and Raulerson, {Chelsea K.} and Yasrab Raza and Xinyu Yan and Parker, {Stephen C. J.} and Johanna Kuusisto and P{\"a}ivi Pajukanta and Jaakko Tuomilehto and Collins, {Francis S.} and Michael Boehnke and Love, {Michael I.} and Koistinen, {Heikki A.} and Markku Laakso and Mohlke, {Karen L.} and Small, {Kerrin S.} and Scott, {Laura J.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = jan,

doi = "10.1038/s41588-024-01982-6",

language = "English",

volume = "57",

pages = "180--192",

journal = "Nature Genetics",

issn = "1061-4036",

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Brotman, SM, El-Sayed Moustafa, JS, Guan, L, Broadaway, KA, Wang, D, Jackson, AU, Welch, R, Currin, KW, Tomlinson, M, Vadlamudi, S, Stringham, HM, Roberts, AL, Lakka, TA, Oravilahti, A, Fernandes Silva, L, Narisu, N, Erdos, MR, Yan, T, Bonnycastle, LL, Raulerson, CK, Raza, Y , Yan, X, Parker, SCJ, Kuusisto, J, Pajukanta, P, Tuomilehto, J, Collins, FS, Boehnke, M, Love, MI, Koistinen, HA, Laakso, M, Mohlke, KL, Small, KS & Scott, LJ 2025, 'Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.', Nature Genetics, vol. 57, no. 1, e1000888, pp. 180-192. https://doi.org/10.1038/s41588-024-01982-6

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T1 - Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

AU - Brotman, Sarah M.

AU - El-Sayed Moustafa, Julia S.

AU - Guan, Li

AU - Broadaway, K. Alaine

AU - Wang, Dongmeng

AU - Jackson, Anne U.

AU - Welch, Ryan

AU - Currin, Kevin W.

AU - Tomlinson, Max

AU - Vadlamudi, Swarooparani

AU - Stringham, Heather M.

AU - Roberts, Amy L.

AU - Lakka, Timo A.

AU - Oravilahti, Anniina

AU - Fernandes Silva, Lilian

AU - Narisu, Narisu

AU - Erdos, Michael R.

AU - Yan, Tingfen

AU - Bonnycastle, Lori L.

AU - Raulerson, Chelsea K.

AU - Raza, Yasrab

AU - Yan, Xinyu

AU - Parker, Stephen C. J.

AU - Kuusisto, Johanna

AU - Pajukanta, Päivi

AU - Tuomilehto, Jaakko

AU - Collins, Francis S.

AU - Boehnke, Michael

AU - Love, Michael I.

AU - Koistinen, Heikki A.

AU - Laakso, Markku

AU - Mohlke, Karen L.

AU - Small, Kerrin S.

AU - Scott, Laura J.

PY - 2025/1

Y1 - 2025/1

N2 - Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS–eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS–eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

AB - Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS–eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS–eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

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U2 - 10.1038/s41588-024-01982-6

DO - 10.1038/s41588-024-01982-6

M3 - Article

SN - 1061-4036

VL - 57

SP - 180

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JO - Nature Genetics

JF - Nature Genetics

IS - 1

M1 - e1000888

ER -

Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

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