A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus

Zubin H. Patel, Xiaoming Lu, Daniel Miller, Carmy R. Forney, Joshua Lee, Arthur Lynch, Connor Schroeder, Lois Parks, Albert F. Magnusen, Xiaoting Chen, Mario Pujato, Avery Maddox, Erin E. Zoller, Bahram Namjou, Hermine I. Brunner, Michael Henrickson, Jennifer L. Huggins, Adrienne H. Williams, Julie T. Ziegler, Mary E. Comeau & 49 others Miranda C. Marion, Stuart B. Glenn, Adam Adler, Nan Shen, Swapan K. Nath, Anne M. Stevens, Barry I. Freedman, Bernardo A. Pons-Estel, Betty P. Tsao, Chaim O. Jacob, Diane L. Kamen, Elizabeth E. Brown, Gary S. Gilkeson, Graciela S. Alarcón, Javier Martin, John D. Reveille, Juan Manuel Anaya, Judith A. James, Kathy L. Sivils, Lindsey A. Criswell, Luis M. Vilá, Michelle Petri, R. Hal Scofield, Robert P. Kimberly, Jeffrey C. Edberg, Rosalind Ramsey-Goldman, So Young Bang, Hye Soon Lee, Sang Cheol Bae, Susan A. Boackle, Deborah Cunninghame Graham, Timothy J. Vyse, Joan T. Merrill, Timothy B. Niewold, Hannah C. Ainsworth, Earl D. Silverman, Michael H. Weisman, Daniel J. Wallace, Prithvi Raj, Joel M. Guthridge, Patrick M. Gaffney, Jennifer A. Kelly, Marta E. Alarcón-Riquelme, Carl D. Langefeld, Edward K. Wakeland, Kenneth M. Kaufman, Matthew T. Weirauch, John B. Harley, Leah C. Kottyan

Research output: Contribution to journalArticle

Abstract

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

Original languageEnglish (US)
Pages (from-to)2392-2404
Number of pages13
JournalHuman Molecular Genetics
Volume27
Issue number13
DOIs
StatePublished - Jul 1 2018

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Alleles
AT-Hook Motifs
B-Lymphocytes
Transcription Factors
Genetic Databases
Genetic Loci
Bayes Theorem
Quantitative Trait Loci
DNA
Systemic Lupus Erythematosus
Introns
Autoimmune Diseases
Chronic Disease
Genotype
Inflammation
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Patel, Z. H., Lu, X., Miller, D., Forney, C. R., Lee, J., Lynch, A., ... Kottyan, L. C. (2018). A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Human Molecular Genetics, 27(13), 2392-2404. https://doi.org/10.1093/hmg/ddy140

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. / Patel, Zubin H.; Lu, Xiaoming; Miller, Daniel; Forney, Carmy R.; Lee, Joshua; Lynch, Arthur; Schroeder, Connor; Parks, Lois; Magnusen, Albert F.; Chen, Xiaoting; Pujato, Mario; Maddox, Avery; Zoller, Erin E.; Namjou, Bahram; Brunner, Hermine I.; Henrickson, Michael; Huggins, Jennifer L.; Williams, Adrienne H.; Ziegler, Julie T.; Comeau, Mary E.; Marion, Miranda C.; Glenn, Stuart B.; Adler, Adam; Shen, Nan; Nath, Swapan K.; Stevens, Anne M.; Freedman, Barry I.; Pons-Estel, Bernardo A.; Tsao, Betty P.; Jacob, Chaim O.; Kamen, Diane L.; Brown, Elizabeth E.; Gilkeson, Gary S.; Alarcón, Graciela S.; Martin, Javier; Reveille, John D.; Anaya, Juan Manuel; James, Judith A.; Sivils, Kathy L.; Criswell, Lindsey A.; Vilá, Luis M.; Petri, Michelle; Scofield, R. Hal; Kimberly, Robert P.; Edberg, Jeffrey C.; Ramsey-Goldman, Rosalind; Bang, So Young; Lee, Hye Soon; Bae, Sang Cheol; Boackle, Susan A.; Graham, Deborah Cunninghame; Vyse, Timothy J.; Merrill, Joan T.; Niewold, Timothy B.; Ainsworth, Hannah C.; Silverman, Earl D.; Weisman, Michael H.; Wallace, Daniel J.; Raj, Prithvi; Guthridge, Joel M.; Gaffney, Patrick M.; Kelly, Jennifer A.; Alarcón-Riquelme, Marta E.; Langefeld, Carl D.; Wakeland, Edward K.; Kaufman, Kenneth M.; Weirauch, Matthew T.; Harley, John B.; Kottyan, Leah C.

In: Human Molecular Genetics, Vol. 27, No. 13, 01.07.2018, p. 2392-2404.

Research output: Contribution to journalArticle

Patel, ZH, Lu, X, Miller, D, Forney, CR, Lee, J, Lynch, A, Schroeder, C, Parks, L, Magnusen, AF, Chen, X, Pujato, M, Maddox, A, Zoller, EE, Namjou, B, Brunner, HI, Henrickson, M, Huggins, JL, Williams, AH, Ziegler, JT, Comeau, ME, Marion, MC, Glenn, SB, Adler, A, Shen, N, Nath, SK, Stevens, AM, Freedman, BI, Pons-Estel, BA, Tsao, BP, Jacob, CO, Kamen, DL, Brown, EE, Gilkeson, GS, Alarcón, GS, Martin, J, Reveille, JD, Anaya, JM, James, JA, Sivils, KL, Criswell, LA, Vilá, LM, Petri, M, Scofield, RH, Kimberly, RP, Edberg, JC, Ramsey-Goldman, R, Bang, SY, Lee, HS, Bae, SC, Boackle, SA, Graham, DC, Vyse, TJ, Merrill, JT, Niewold, TB, Ainsworth, HC, Silverman, ED, Weisman, MH, Wallace, DJ, Raj, P, Guthridge, JM, Gaffney, PM, Kelly, JA, Alarcón-Riquelme, ME, Langefeld, CD, Wakeland, EK, Kaufman, KM, Weirauch, MT, Harley, JB & Kottyan, LC 2018, 'A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus', Human Molecular Genetics, vol. 27, no. 13, pp. 2392-2404. https://doi.org/10.1093/hmg/ddy140
Patel, Zubin H. ; Lu, Xiaoming ; Miller, Daniel ; Forney, Carmy R. ; Lee, Joshua ; Lynch, Arthur ; Schroeder, Connor ; Parks, Lois ; Magnusen, Albert F. ; Chen, Xiaoting ; Pujato, Mario ; Maddox, Avery ; Zoller, Erin E. ; Namjou, Bahram ; Brunner, Hermine I. ; Henrickson, Michael ; Huggins, Jennifer L. ; Williams, Adrienne H. ; Ziegler, Julie T. ; Comeau, Mary E. ; Marion, Miranda C. ; Glenn, Stuart B. ; Adler, Adam ; Shen, Nan ; Nath, Swapan K. ; Stevens, Anne M. ; Freedman, Barry I. ; Pons-Estel, Bernardo A. ; Tsao, Betty P. ; Jacob, Chaim O. ; Kamen, Diane L. ; Brown, Elizabeth E. ; Gilkeson, Gary S. ; Alarcón, Graciela S. ; Martin, Javier ; Reveille, John D. ; Anaya, Juan Manuel ; James, Judith A. ; Sivils, Kathy L. ; Criswell, Lindsey A. ; Vilá, Luis M. ; Petri, Michelle ; Scofield, R. Hal ; Kimberly, Robert P. ; Edberg, Jeffrey C. ; Ramsey-Goldman, Rosalind ; Bang, So Young ; Lee, Hye Soon ; Bae, Sang Cheol ; Boackle, Susan A. ; Graham, Deborah Cunninghame ; Vyse, Timothy J. ; Merrill, Joan T. ; Niewold, Timothy B. ; Ainsworth, Hannah C. ; Silverman, Earl D. ; Weisman, Michael H. ; Wallace, Daniel J. ; Raj, Prithvi ; Guthridge, Joel M. ; Gaffney, Patrick M. ; Kelly, Jennifer A. ; Alarcón-Riquelme, Marta E. ; Langefeld, Carl D. ; Wakeland, Edward K. ; Kaufman, Kenneth M. ; Weirauch, Matthew T. ; Harley, John B. ; Kottyan, Leah C. / A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 13. pp. 2392-2404.
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abstract = "Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.",
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AU - Patel, Zubin H.

AU - Lu, Xiaoming

AU - Miller, Daniel

AU - Forney, Carmy R.

AU - Lee, Joshua

AU - Lynch, Arthur

AU - Schroeder, Connor

AU - Parks, Lois

AU - Magnusen, Albert F.

AU - Chen, Xiaoting

AU - Pujato, Mario

AU - Maddox, Avery

AU - Zoller, Erin E.

AU - Namjou, Bahram

AU - Brunner, Hermine I.

AU - Henrickson, Michael

AU - Huggins, Jennifer L.

AU - Williams, Adrienne H.

AU - Ziegler, Julie T.

AU - Comeau, Mary E.

AU - Marion, Miranda C.

AU - Glenn, Stuart B.

AU - Adler, Adam

AU - Shen, Nan

AU - Nath, Swapan K.

AU - Stevens, Anne M.

AU - Freedman, Barry I.

AU - Pons-Estel, Bernardo A.

AU - Tsao, Betty P.

AU - Jacob, Chaim O.

AU - Kamen, Diane L.

AU - Brown, Elizabeth E.

AU - Gilkeson, Gary S.

AU - Alarcón, Graciela S.

AU - Martin, Javier

AU - Reveille, John D.

AU - Anaya, Juan Manuel

AU - James, Judith A.

AU - Sivils, Kathy L.

AU - Criswell, Lindsey A.

AU - Vilá, Luis M.

AU - Petri, Michelle

AU - Scofield, R. Hal

AU - Kimberly, Robert P.

AU - Edberg, Jeffrey C.

AU - Ramsey-Goldman, Rosalind

AU - Bang, So Young

AU - Lee, Hye Soon

AU - Bae, Sang Cheol

AU - Boackle, Susan A.

AU - Graham, Deborah Cunninghame

AU - Vyse, Timothy J.

AU - Merrill, Joan T.

AU - Niewold, Timothy B.

AU - Ainsworth, Hannah C.

AU - Silverman, Earl D.

AU - Weisman, Michael H.

AU - Wallace, Daniel J.

AU - Raj, Prithvi

AU - Guthridge, Joel M.

AU - Gaffney, Patrick M.

AU - Kelly, Jennifer A.

AU - Alarcón-Riquelme, Marta E.

AU - Langefeld, Carl D.

AU - Wakeland, Edward K.

AU - Kaufman, Kenneth M.

AU - Weirauch, Matthew T.

AU - Harley, John B.

AU - Kottyan, Leah C.

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N2 - Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

AB - Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

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