Systematic identification of trans eQTLs as putative drivers of known disease associations

HJ Westra; Marjolein Peters; T Esko; H Yaghootkar; C Schurmann; J Kettunen; MW Christiansen; BP Fairfax; K Schramm; JE Powell; A Zhernakova; DV Zhernakova; JH Veldink; LH van den Berg; J Karjalainen; S Withoff; André Uitterlinden; Bert Hofman; Fernando Rivadeneira; PAC 't Hoen; E Reinmaa; K (Kirsten) Fischer; M Nelis; L Milani; D Melzer; L Ferrucci; AB Singleton; DG Hernandez; MA Nalls; G Homuth; M Nauck; D Radke; U Volker; M Perola; V Salomaa; J Brody; A Suchy-Dicey; SA Gharib; DA Enquobahrie; T Lumley; GW Montgomery; S Makino; H Prokisch; Cindy Herder; M Roden; H Grallert; T Meitinger; K Strauch; Y Li; RC Jansen; PM Visscher; JC Knight; BM Psaty; S Ripatti; A Teumer; TM Frayling; A Metspalu; Joyce van Meurs; L Franke

doi:10.1038/ng.2756

Systematic identification of trans eQTLs as putative drivers of known disease associations

HJ Westra, Marjolein Peters, T Esko, H Yaghootkar, C Schurmann, J Kettunen, MW Christiansen, BP Fairfax, K Schramm, JE Powell, A Zhernakova, DV Zhernakova, JH Veldink, LH van den Berg, J Karjalainen, S Withoff, André Uitterlinden, Bert Hofman, Fernando Rivadeneira, PAC 't HoenE Reinmaa, K (Kirsten) Fischer, M Nelis, L Milani, D Melzer, L Ferrucci, AB Singleton, DG Hernandez, MA Nalls, G Homuth, M Nauck, D Radke, U Volker, M Perola, V Salomaa, J Brody, A Suchy-Dicey, SA Gharib, DA Enquobahrie, T Lumley, GW Montgomery, S Makino, H Prokisch, Cindy Herder, M Roden, H Grallert, T Meitinger, K Strauch, Y Li, RC Jansen, PM Visscher, JC Knight, BM Psaty, S Ripatti, A Teumer, TM Frayling, A Metspalu, Joyce van Meurs, L Franke

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Abstract

Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE)(1), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE2-4. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

Original language	Undefined/Unknown
Pages (from-to)	1238-U195
Journal	Nature Genetics
Volume	45
Issue number	10
DOIs	https://doi.org/10.1038/ng.2756
Publication status	Published - 2013

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EMC MM-01-39-09-A
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10.1038/ng.2756

http://hdl.handle.net/1765/41367

Cite this

Westra, HJ., Peters, M., Esko, T., Yaghootkar, H., Schurmann, C., Kettunen, J., Christiansen, MW., Fairfax, BP., Schramm, K., Powell, JE., Zhernakova, A., Zhernakova, DV., Veldink, JH., van den Berg, LH., Karjalainen, J., Withoff, S., Uitterlinden, A., Hofman, B., Rivadeneira, F., ... Franke, L. (2013). Systematic identification of trans eQTLs as putative drivers of known disease associations. Nature Genetics, 45(10), 1238-U195. https://doi.org/10.1038/ng.2756

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abstract = "Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE)(1), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE2-4. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.",

author = "HJ Westra and Marjolein Peters and T Esko and H Yaghootkar and C Schurmann and J Kettunen and MW Christiansen and BP Fairfax and K Schramm and JE Powell and A Zhernakova and DV Zhernakova and JH Veldink and \{van den Berg\}, LH and J Karjalainen and S Withoff and Andr{\'e} Uitterlinden and Bert Hofman and Fernando Rivadeneira and \{'t Hoen\}, PAC and E Reinmaa and Fischer, \{K (Kirsten)\} and M Nelis and L Milani and D Melzer and L Ferrucci and AB Singleton and DG Hernandez and MA Nalls and G Homuth and M Nauck and D Radke and U Volker and M Perola and V Salomaa and J Brody and A Suchy-Dicey and SA Gharib and DA Enquobahrie and T Lumley and GW Montgomery and S Makino and H Prokisch and Cindy Herder and M Roden and H Grallert and T Meitinger and K Strauch and Y Li and RC Jansen and PM Visscher and JC Knight and BM Psaty and S Ripatti and A Teumer and TM Frayling and A Metspalu and \{van Meurs\}, Joyce and L Franke",

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Westra, HJ, Peters, M, Esko, T, Yaghootkar, H, Schurmann, C, Kettunen, J, Christiansen, MW, Fairfax, BP, Schramm, K, Powell, JE, Zhernakova, A, Zhernakova, DV, Veldink, JH, van den Berg, LH, Karjalainen, J, Withoff, S, Uitterlinden, A, Hofman, B , Rivadeneira, F, 't Hoen, PAC, Reinmaa, E, Fischer, K, Nelis, M, Milani, L, Melzer, D, Ferrucci, L, Singleton, AB, Hernandez, DG, Nalls, MA, Homuth, G, Nauck, M, Radke, D, Volker, U, Perola, M, Salomaa, V, Brody, J, Suchy-Dicey, A, Gharib, SA, Enquobahrie, DA, Lumley, T, Montgomery, GW, Makino, S, Prokisch, H, Herder, C, Roden, M, Grallert, H, Meitinger, T, Strauch, K, Li, Y, Jansen, RC, Visscher, PM, Knight, JC, Psaty, BM, Ripatti, S, Teumer, A, Frayling, TM, Metspalu, A, van Meurs, J & Franke, L 2013, 'Systematic identification of trans eQTLs as putative drivers of known disease associations', Nature Genetics, vol. 45, no. 10, pp. 1238-U195. https://doi.org/10.1038/ng.2756

TY - JOUR

T1 - Systematic identification of trans eQTLs as putative drivers of known disease associations

AU - Westra, HJ

AU - Peters, Marjolein

AU - Esko, T

AU - Yaghootkar, H

AU - Schurmann, C

AU - Kettunen, J

AU - Christiansen, MW

AU - Fairfax, BP

AU - Schramm, K

AU - Powell, JE

AU - Zhernakova, A

AU - Zhernakova, DV

AU - Veldink, JH

AU - van den Berg, LH

AU - Karjalainen, J

AU - Withoff, S

AU - Uitterlinden, André

AU - Hofman, Bert

AU - Rivadeneira, Fernando

AU - 't Hoen, PAC

AU - Reinmaa, E

AU - Fischer, K (Kirsten)

AU - Nelis, M

AU - Milani, L

AU - Melzer, D

AU - Ferrucci, L

AU - Singleton, AB

AU - Hernandez, DG

AU - Nalls, MA

AU - Homuth, G

AU - Nauck, M

AU - Radke, D

AU - Volker, U

AU - Perola, M

AU - Salomaa, V

AU - Brody, J

AU - Suchy-Dicey, A

AU - Gharib, SA

AU - Enquobahrie, DA

AU - Lumley, T

AU - Montgomery, GW

AU - Makino, S

AU - Prokisch, H

AU - Herder, Cindy

AU - Roden, M

AU - Grallert, H

AU - Meitinger, T

AU - Strauch, K

AU - Li, Y

AU - Jansen, RC

AU - Visscher, PM

AU - Knight, JC

AU - Psaty, BM

AU - Ripatti, S

AU - Teumer, A

AU - Frayling, TM

AU - Metspalu, A

AU - van Meurs, Joyce

AU - Franke, L

PY - 2013

Y1 - 2013

N2 - Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE)(1), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE2-4. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

AB - Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE)(1), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE2-4. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.

U2 - 10.1038/ng.2756

DO - 10.1038/ng.2756

M3 - Article

C2 - 24013639

SN - 1061-4036

VL - 45

SP - 1238-U195

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -