Sarah A Gagliano Taliun1,2,3, Patrick Sulem4, Gardar Sveinbjornsson4, Daniel F Gudbjartsson4, Kari Stefansson4,5, Andrew D Paterson6,7,8,9, Moumita Barua10,11,12,13. 1. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. 2. Department of Neurosciences, Université de Montréal, Montreal, Quebec, Canada. 3. Research Centre, Montréal Heart Institute, Montreal, Quebec, Canada. 4. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. 5. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 6. Division of Epidemiology, Dalla Lana School of Public Health, Toronto, Ontario, Canada andrew.paterson@sickkids.ca moumita.barua@uhn.ca. 7. Division of Biostatistics, Dalla Lana School of Public Health, Toronto, Ontario, Canada. 8. Genetics and Genome Biology, Research Institute at The Hospital for Sick Children, Toronto, Ontario, Canada. 9. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada. 10. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada andrew.paterson@sickkids.ca moumita.barua@uhn.ca. 11. Division of Nephrology, University Health Network, Toronto, Ontario, Canada. 12. Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 13. Toronto General Hospital Research Institute, Toronto, Ontario, Canada.
Abstract
BACKGROUND AND OBJECTIVES: Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hematuria were enriched by excluding participants with genitourinary conditions. A strongly associated locus on chromosome 2 (COL4A4-COL4A3) was identified. The region was reimputed using the Trans-Omics for Precision Medicine Program followed by sequential rounds of regional conditional analysis, conditioning on previous genetic signals. Similarly, we applied conditional analysis to identify independent variants in the MHC region on chromosome 6 using imputed HLA haplotypes. RESULTS: In total, 16,866 hematuria cases and 391,420 controls were included. Cases had higher urinary albumin-creatinine compared with controls (women: 13.01 mg/g [8.05-21.33] versus 12.12 mg/g [7.61-19.29]; P<0.001; men: 8.85 mg/g [5.66-16.19] versus 7.52 mg/g [5.04-12.39]; P<0.001) and lower eGFR (women: 88±14 versus 90±13 ml/min per 1.72 m2; P<0.001; men: 87±15 versus 90±13 ml/min per 1.72 m2; P<0.001), supporting enrichment of glomerular hematuria. Variants at six loci (PDPN, COL4A4-COL4A3, HLA-B, SORL1, PLLP, and TGFB1) met genome-wide significance (P<5E-8). At chromosome 2, COL4A4 p.Ser969X (rs35138315; minor allele frequency=0.00035; P<7.95E-35; odds ratio, 87.3; 95% confidence interval, 47.9 to 159.0) had the most significant association, and two variants in the locus remained associated with hematuria after conditioning for this variant: COL4A3 p.Gly695Arg (rs200287952; minor allele frequency=0.00021; P<2.16E-7; odds ratio, 45.5; 95% confidence interval, 11.8 to 168.0) and a common COL4A4 intron 25 variant (not previously reported; rs58261427; minor allele frequency=0.214; P<2.00E-9; odds ratio, 1.09; 95% confidence interval, 1.06 to 1.12). Of the HLA haplotypes, HLA-B (*0801; minor allele frequency=0.14; P<4.41E-24; odds ratio, 0.84; 95% confidence interval, 0.82 to 0.88) displayed the most statistically significant association. For remaining loci, we identified three novel associations, which were replicated in the deCODE dataset for dipstick hematuria (nearest genes: PDPN, SORL1, and PLLP). CONCLUSIONS: Our study identifies six loci associated with hematuria, including independent variants in COL4A4-COL4A3 and HLA-B. Additionally, three novel loci are reported, including an association with an intronic variant in PDPN expressed in the podocyte. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN13711021.mp3.
BACKGROUND AND OBJECTIVES: Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hematuria were enriched by excluding participants with genitourinary conditions. A strongly associated locus on chromosome 2 (COL4A4-COL4A3) was identified. The region was reimputed using the Trans-Omics for Precision Medicine Program followed by sequential rounds of regional conditional analysis, conditioning on previous genetic signals. Similarly, we applied conditional analysis to identify independent variants in the MHC region on chromosome 6 using imputed HLA haplotypes. RESULTS: In total, 16,866 hematuria cases and 391,420 controls were included. Cases had higher urinary albumin-creatinine compared with controls (women: 13.01 mg/g [8.05-21.33] versus 12.12 mg/g [7.61-19.29]; P<0.001; men: 8.85 mg/g [5.66-16.19] versus 7.52 mg/g [5.04-12.39]; P<0.001) and lower eGFR (women: 88±14 versus 90±13 ml/min per 1.72 m2; P<0.001; men: 87±15 versus 90±13 ml/min per 1.72 m2; P<0.001), supporting enrichment of glomerular hematuria. Variants at six loci (PDPN, COL4A4-COL4A3, HLA-B, SORL1, PLLP, and TGFB1) met genome-wide significance (P<5E-8). At chromosome 2, COL4A4 p.Ser969X (rs35138315; minor allele frequency=0.00035; P<7.95E-35; odds ratio, 87.3; 95% confidence interval, 47.9 to 159.0) had the most significant association, and two variants in the locus remained associated with hematuria after conditioning for this variant: COL4A3 p.Gly695Arg (rs200287952; minor allele frequency=0.00021; P<2.16E-7; odds ratio, 45.5; 95% confidence interval, 11.8 to 168.0) and a common COL4A4 intron 25 variant (not previously reported; rs58261427; minor allele frequency=0.214; P<2.00E-9; odds ratio, 1.09; 95% confidence interval, 1.06 to 1.12). Of the HLA haplotypes, HLA-B (*0801; minor allele frequency=0.14; P<4.41E-24; odds ratio, 0.84; 95% confidence interval, 0.82 to 0.88) displayed the most statistically significant association. For remaining loci, we identified three novel associations, which were replicated in the deCODE dataset for dipstick hematuria (nearest genes: PDPN, SORL1, and PLLP). CONCLUSIONS: Our study identifies six loci associated with hematuria, including independent variants in COL4A4-COL4A3 and HLA-B. Additionally, three novel loci are reported, including an association with an intronic variant in PDPN expressed in the podocyte. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_04_26_CJN13711021.mp3.
Authors: Daniela Zanetti; Abhiram Rao; Stefan Gustafsson; Themistocles L Assimes; Stephen B Montgomery; Erik Ingelsson Journal: Kidney Int Date: 2019-03-12 Impact factor: 10.612
Authors: Yang Luo; Masahiro Kanai; Wanson Choi; Xinyi Li; Saori Sakaue; Kenichi Yamamoto; Kotaro Ogawa; Maria Gutierrez-Arcelus; Peter K Gregersen; Philip E Stuart; James T Elder; Lukas Forer; Sebastian Schönherr; Christian Fuchsberger; Albert V Smith; Jacques Fellay; Mary Carrington; David W Haas; Xiuqing Guo; Nicholette D Palmer; Yii-Der Ida Chen; Jerome I Rotter; Kent D Taylor; Stephen S Rich; Adolfo Correa; James G Wilson; Sekar Kathiresan; Michael H Cho; Andres Metspalu; Tonu Esko; Yukinori Okada; Buhm Han; Paul J McLaren; Soumya Raychaudhuri Journal: Nat Genet Date: 2021-10-05 Impact factor: 38.330
Authors: Alexander Dilthey; Stephen Leslie; Loukas Moutsianas; Judong Shen; Charles Cox; Matthew R Nelson; Gil McVean Journal: PLoS Comput Biol Date: 2013-02-14 Impact factor: 4.475
Authors: Daniel Taliun; Daniel N Harris; Michael D Kessler; Jedidiah Carlson; Zachary A Szpiech; Raul Torres; Sarah A Gagliano Taliun; André Corvelo; Stephanie M Gogarten; Hyun Min Kang; Achilleas N Pitsillides; Jonathon LeFaive; Seung-Been Lee; Xiaowen Tian; Brian L Browning; Sayantan Das; Anne-Katrin Emde; Wayne E Clarke; Douglas P Loesch; Amol C Shetty; Thomas W Blackwell; Albert V Smith; Quenna Wong; Xiaoming Liu; Matthew P Conomos; Dean M Bobo; François Aguet; Christine Albert; Alvaro Alonso; Kristin G Ardlie; Dan E Arking; Stella Aslibekyan; Paul L Auer; John Barnard; R Graham Barr; Lucas Barwick; Lewis C Becker; Rebecca L Beer; Emelia J Benjamin; Lawrence F Bielak; John Blangero; Michael Boehnke; Donald W Bowden; Jennifer A Brody; Esteban G Burchard; Brian E Cade; James F Casella; Brandon Chalazan; Daniel I Chasman; Yii-Der Ida Chen; Michael H Cho; Seung Hoan Choi; Mina K Chung; Clary B Clish; Adolfo Correa; Joanne E Curran; Brian Custer; Dawood Darbar; Michelle Daya; Mariza de Andrade; Dawn L DeMeo; Susan K Dutcher; Patrick T Ellinor; Leslie S Emery; Celeste Eng; Diane Fatkin; Tasha Fingerlin; Lukas Forer; Myriam Fornage; Nora Franceschini; Christian Fuchsberger; Stephanie M Fullerton; Soren Germer; Mark T Gladwin; Daniel J Gottlieb; Xiuqing Guo; Michael E Hall; Jiang He; Nancy L Heard-Costa; Susan R Heckbert; Marguerite R Irvin; Jill M Johnsen; Andrew D Johnson; Robert Kaplan; Sharon L R Kardia; Tanika Kelly; Shannon Kelly; Eimear E Kenny; Douglas P Kiel; Robert Klemmer; Barbara A Konkle; Charles Kooperberg; Anna Köttgen; Leslie A Lange; Jessica Lasky-Su; Daniel Levy; Xihong Lin; Keng-Han Lin; Chunyu Liu; Ruth J F Loos; Lori Garman; Robert Gerszten; Steven A Lubitz; Kathryn L Lunetta; Angel C Y Mak; Ani Manichaikul; Alisa K Manning; Rasika A Mathias; David D McManus; Stephen T McGarvey; James B Meigs; Deborah A Meyers; Julie L Mikulla; Mollie A Minear; Braxton D Mitchell; Sanghamitra Mohanty; May E Montasser; Courtney Montgomery; Alanna C Morrison; Joanne M Murabito; Andrea Natale; Pradeep Natarajan; Sarah C Nelson; Kari E North; Jeffrey R O'Connell; Nicholette D Palmer; Nathan Pankratz; Gina M Peloso; Patricia A Peyser; Jacob Pleiness; Wendy S Post; Bruce M Psaty; D C Rao; Susan Redline; Alexander P Reiner; Dan Roden; Jerome I Rotter; Ingo Ruczinski; Chloé Sarnowski; Sebastian Schoenherr; David A Schwartz; Jeong-Sun Seo; Sudha Seshadri; Vivien A Sheehan; Wayne H Sheu; M Benjamin Shoemaker; Nicholas L Smith; Jennifer A Smith; Nona Sotoodehnia; Adrienne M Stilp; Weihong Tang; Kent D Taylor; Marilyn Telen; Timothy A Thornton; Russell P Tracy; David J Van Den Berg; Ramachandran S Vasan; Karine A Viaud-Martinez; Scott Vrieze; Daniel E Weeks; Bruce S Weir; Scott T Weiss; Lu-Chen Weng; Cristen J Willer; Yingze Zhang; Xutong Zhao; Donna K Arnett; Allison E Ashley-Koch; Kathleen C Barnes; Eric Boerwinkle; Stacey Gabriel; Richard Gibbs; Kenneth M Rice; Stephen S Rich; Edwin K Silverman; Pankaj Qasba; Weiniu Gan; George J Papanicolaou; Deborah A Nickerson; Sharon R Browning; Michael C Zody; Sebastian Zöllner; James G Wilson; L Adrienne Cupples; Cathy C Laurie; Cashell E Jaquish; Ryan D Hernandez; Timothy D O'Connor; Gonçalo R Abecasis Journal: Nature Date: 2021-02-10 Impact factor: 69.504