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Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidenc... Full description

Journal Title: American Journal of Human Genetics 2016, Vol. 99(3), pp. 636-646
Main Author: Mahajan, Anubha
Other Authors: Rodan, Aylin R. , Le, Thu H. , Gaulton, Kyle J. , Haessler, Jeffrey , Stilp, Adrienne M. , Kamatani, Yoichiro , Zhu, Gu , Sofer, Tamar , Puri, Sanjana , Schellinger, Jeffrey N. , Chu, Pei-Lun , Cechova, Sylvia , van Zuydam, Natalie , Ärnlöv, Johan , Flessner, Michael F. , Giedraitis, Vilmantas , Heath, Andrew C. , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia M. , Madden, Pamela A. F. , Montgomery, Grant W. , Papanicolaou, George J. , Reiner, Alex P. , Sundström, Johan , Thornton, Timothy A. , Lind, Lars , Ingelsson, Erik , Cai, Jianwen , Martin, Nicholas G. , Kooperberg, Charles , Matsuda, Koichi , Whitfield, John B. , Okada, Yukinori , Laurie, Cathy C. , Morris, Andrew P. , Franceschini, Nora
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0002-9297 ; DOI: 10.1016/j.ajhg.2016.07.012
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-303900
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title: Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
format: Article
creator:
  • Mahajan, Anubha
  • Rodan, Aylin R.
  • Le, Thu H.
  • Gaulton, Kyle J.
  • Haessler, Jeffrey
  • Stilp, Adrienne M.
  • Kamatani, Yoichiro
  • Zhu, Gu
  • Sofer, Tamar
  • Puri, Sanjana
  • Schellinger, Jeffrey N.
  • Chu, Pei-Lun
  • Cechova, Sylvia
  • van Zuydam, Natalie
  • Ärnlöv, Johan
  • Flessner, Michael F.
  • Giedraitis, Vilmantas
  • Heath, Andrew C.
  • Kubo, Michiaki
  • Larsson, Anders
  • Lindgren, Cecilia M.
  • Madden, Pamela A. F.
  • Montgomery, Grant W.
  • Papanicolaou, George J.
  • Reiner, Alex P.
  • Sundström, Johan
  • Thornton, Timothy A.
  • Lind, Lars
  • Ingelsson, Erik
  • Cai, Jianwen
  • Martin, Nicholas G.
  • Kooperberg, Charles
  • Matsuda, Koichi
  • Whitfield, John B.
  • Okada, Yukinori
  • Laurie, Cathy C.
  • Morris, Andrew P.
  • Franceschini, Nora
subjects:
  • Medical And Health Sciences
  • Clinical Medicine
  • Urology And Nephrology
  • Medicin Och Hälsovetenskap
  • Klinisk Medicin
  • Urologi Och Njurmedicin
ispartof: American Journal of Human Genetics, 2016, Vol. 99(3), pp. 636-646
description: We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
language: eng
source:
identifier: ISSN: 0002-9297 ; DOI: 10.1016/j.ajhg.2016.07.012
fulltext: fulltext_linktorsrc
issn:
  • 00029297
  • 0002-9297
url: Link


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titleTrans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
creatorMahajan, Anubha ; Rodan, Aylin R. ; Le, Thu H. ; Gaulton, Kyle J. ; Haessler, Jeffrey ; Stilp, Adrienne M. ; Kamatani, Yoichiro ; Zhu, Gu ; Sofer, Tamar ; Puri, Sanjana ; Schellinger, Jeffrey N. ; Chu, Pei-Lun ; Cechova, Sylvia ; van Zuydam, Natalie ; Ärnlöv, Johan ; Flessner, Michael F. ; Giedraitis, Vilmantas ; Heath, Andrew C. ; Kubo, Michiaki ; Larsson, Anders ; Lindgren, Cecilia M. ; Madden, Pamela A. F. ; Montgomery, Grant W. ; Papanicolaou, George J. ; Reiner, Alex P. ; Sundström, Johan ; Thornton, Timothy A. ; Lind, Lars ; Ingelsson, Erik ; Cai, Jianwen ; Martin, Nicholas G. ; Kooperberg, Charles ; Matsuda, Koichi ; Whitfield, John B. ; Okada, Yukinori ; Laurie, Cathy C. ; Morris, Andrew P. ; Franceschini, Nora
contributorUppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi ; Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik ; Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion ; Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi ; Uppsala universitet, Science for Life Laboratory, SciLifeLab, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
ispartofAmerican Journal of Human Genetics, 2016, Vol. 99(3), pp. 636-646
identifierISSN: 0002-9297 ; DOI: 10.1016/j.ajhg.2016.07.012
subjectMedical And Health Sciences ; Clinical Medicine ; Urology And Nephrology ; Medicin Och Hälsovetenskap ; Klinisk Medicin ; Urologi Och Njurmedicin
descriptionWe analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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7Zhu, Gu
8Sofer, Tamar
9Puri, Sanjana
10Schellinger, Jeffrey N.
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14Ärnlöv, Johan
15Flessner, Michael F.
16Giedraitis, Vilmantas
17Heath, Andrew C.
18Kubo, Michiaki
19Larsson, Anders
20Lindgren, Cecilia M.
21Madden, Pamela A. F.
22Montgomery, Grant W.
23Papanicolaou, George J.
24Reiner, Alex P.
25Sundström, Johan
26Thornton, Timothy A.
27Lind, Lars
28Ingelsson, Erik
29Cai, Jianwen
30Martin, Nicholas G.
31Kooperberg, Charles
32Matsuda, Koichi
33Whitfield, John B.
34Okada, Yukinori
35Laurie, Cathy C.
36Morris, Andrew P.
37Franceschini, Nora
38Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi
39Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik
40Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion
41Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
42Uppsala universitet, Science for Life Laboratory, SciLifeLab, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
titleTrans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
descriptionWe analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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0Medical And Health Sciences
1Clinical Medicine
2Urology And Nephrology
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4Klinisk Medicin
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titleTrans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
authorMahajan, Anubha ; Rodan, Aylin R. ; Le, Thu H. ; Gaulton, Kyle J. ; Haessler, Jeffrey ; Stilp, Adrienne M. ; Kamatani, Yoichiro ; Zhu, Gu ; Sofer, Tamar ; Puri, Sanjana ; Schellinger, Jeffrey N. ; Chu, Pei-Lun ; Cechova, Sylvia ; van Zuydam, Natalie ; Ärnlöv, Johan ; Flessner, Michael F. ; Giedraitis, Vilmantas ; Heath, Andrew C. ; Kubo, Michiaki ; Larsson, Anders ; Lindgren, Cecilia M. ; Madden, Pamela A. F. ; Montgomery, Grant W. ; Papanicolaou, George J. ; Reiner, Alex P. ; Sundström, Johan ; Thornton, Timothy A. ; Lind, Lars ; Ingelsson, Erik ; Cai, Jianwen ; Martin, Nicholas G. ; Kooperberg, Charles ; Matsuda, Koichi ; Whitfield, John B. ; Okada, Yukinori ; Laurie, Cathy C. ; Morris, Andrew P. ; Franceschini, Nora
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1Rodan, Aylin R.
2Le, Thu H.
3Gaulton, Kyle J.
4Haessler, Jeffrey
5Stilp, Adrienne M.
6Kamatani, Yoichiro
7Zhu, Gu
8Sofer, Tamar
9Puri, Sanjana
10Schellinger, Jeffrey N.
11Chu, Pei-Lun
12Cechova, Sylvia
13van Zuydam, Natalie
14Ärnlöv, Johan
15Flessner, Michael F.
16Giedraitis, Vilmantas
17Heath, Andrew C.
18Kubo, Michiaki
19Larsson, Anders
20Lindgren, Cecilia M.
21Madden, Pamela A. F.
22Montgomery, Grant W.
23Papanicolaou, George J.
24Reiner, Alex P.
25Sundström, Johan
26Thornton, Timothy A.
27Lind, Lars
28Ingelsson, Erik
29Cai, Jianwen
30Martin, Nicholas G.
31Kooperberg, Charles
32Matsuda, Koichi
33Whitfield, John B.
34Okada, Yukinori
35Laurie, Cathy C.
36Morris, Andrew P.
37Franceschini, Nora
38Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi
39Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik
40Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion
41Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
42Uppsala universitet, Science for Life Laboratory, SciLifeLab, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
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4Jeffrey
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6Yoichiro
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13Natalie
14Johan
15Michael F.
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19Anders
20Cecilia M.
21Pamela A. F.
22Grant W.
23George J.
24Alex P.
25Timothy A.
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1Rodan, Aylin R.
2Le, Thu H.
3Gaulton, Kyle J.
4Haessler, Jeffrey
5Stilp, Adrienne M.
6Kamatani, Yoichiro
7Zhu, Gu
8Sofer, Tamar
9Puri, Sanjana
10Schellinger, Jeffrey N.
11Chu, Pei-Lun
12Cechova, Sylvia
13van Zuydam, Natalie
14Ärnlöv, Johan
15Flessner, Michael F.
16Giedraitis, Vilmantas
17Heath, Andrew C.
18Kubo, Michiaki
19Larsson, Anders
20Lindgren, Cecilia M.
21Madden, Pamela A. F.
22Montgomery, Grant W.
23Papanicolaou, George J.
24Reiner, Alex P.
25Sundström, Johan
26Thornton, Timothy A.
27Lind, Lars
28Ingelsson, Erik
29Cai, Jianwen
30Martin, Nicholas G.
31Kooperberg, Charles
32Matsuda, Koichi
33Whitfield, John B.
34Okada, Yukinori
35Laurie, Cathy C.
36Morris, Andrew P.
37Franceschini, Nora
aucorp
0Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi
1Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik
2Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion
3Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
4Uppsala universitet, Science for Life Laboratory, SciLifeLab, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi
atitleTrans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity
jtitleAmerican Journal of Human Genetics
date2016
risdate2016
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pages636-646
issn0002-9297
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abstractWe analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
doi10.1016/j.ajhg.2016.07.012
eissn15376605
oafree_for_read