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1. Apolipoprotein L1 (APOL1) renal risk variant-mediated podocyte cytotoxicity depends on African haplotype and surface expression

Author

Nidhi Gupta, Bridget Waas, Daniel Austin, Ann M. De Mazière, Pekka Kujala, Amy D. Stockwell, Tianbo Li, Brian L. Yaspan, Judith Klumperman, and Suzie J. Scales

Subjects
Medicine, Science
Abstract

Abstract Homozygous Apolipoprotein L1 (APOL1) variants G1 and G2 cause APOL1-mediated kidney disease, purportedly acting as surface cation channels in podocytes. APOL1-G0 exhibits various single nucleotide polymorphisms, most commonly haplotype E150K, M228I and R255K (“KIK”; the Reference Sequence is “EMR”), whereas variants G1 and G2 are mostly found in a single “African” haplotype background (“EIK”). Several labs reported cytotoxicity with risk variants G1 and G2 in KIK or EIK background haplotypes, but used HEK-293 cells and did not verify equal surface expression. To see if haplotype matters in a more relevant cell type, we induced APOL1-G0, G1 and G2 EIK, KIK and EMR at comparable surface levels in immortalized podocytes. G1 and G2 risk variants (but not G0) caused dose-dependent podocyte death within 48h only in their native African EIK haplotype and correlated with K+ conductance (thallium FLIPR). We ruled out differences in localization and trafficking, except for possibly greater surface clustering of cytotoxic haplotypes. APOL1 surface expression was required, since Brefeldin A rescued cytotoxicity; and cytoplasmic isoforms vB3 and vC were not cytotoxic. Thus, APOL1-EIK risk variants kill podocytes in a dose and haplotype-dependent manner (as in HEK-293 cells), whereas unlike in HEK-293 cells the KIK risk variants did not.

Published
2024
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2. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Author

Guillaume Butler-Laporte, Gundula Povysil, Jack A Kosmicki, Elizabeth T Cirulli, Theodore Drivas, Simone Furini, Chadi Saad, Axel Schmidt, Pawel Olszewski, Urszula Korotko, Mathieu Quinodoz, Elifnaz Çelik, Kousik Kundu, Klaudia Walter, Junghyun Jung, Amy D Stockwell, Laura G Sloofman, Daniel M Jordan, Ryan C Thompson, Diane Del Valle, Nicole Simons, Esther Cheng, Robert Sebra, Eric E Schadt, Seunghee Kim-Schulze, Sacha Gnjatic, Miriam Merad, Joseph D Buxbaum, Noam D Beckmann, Alexander W Charney, Bartlomiej Przychodzen, Timothy Chang, Tess D Pottinger, Ning Shang, Fabian Brand, Francesca Fava, Francesca Mari, Karolina Chwialkowska, Magdalena Niemira, Szymon Pula, J Kenneth Baillie, Alex Stuckey, Antonio Salas, Xabier Bello, Jacobo Pardo-Seco, Alberto Gómez-Carballa, Irene Rivero-Calle, Federico Martinón-Torres, Andrea Ganna, Konrad J Karczewski, Kumar Veerapen, Mathieu Bourgey, Guillaume Bourque, Robert Jm Eveleigh, Vincenzo Forgetta, David Morrison, David Langlais, Mark Lathrop, Vincent Mooser, Tomoko Nakanishi, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Yanara Marincevic-Zuniga, Jessica Nordlund, Kelly M Schiabor Barrett, William Lee, Alexandre Bolze, Simon White, Stephen Riffle, Francisco Tanudjaja, Efren Sandoval, Iva Neveux, Shaun Dabe, Nicolas Casadei, Susanne Motameny, Manal Alaamery, Salam Massadeh, Nora Aljawini, Mansour S Almutairi, Yaseen M Arabi, Saleh A Alqahtani, Fawz S Al Harthi, Amal Almutairi, Fatima Alqubaishi, Sarah Alotaibi, Albandari Binowayn, Ebtehal A Alsolm, Hadeel El Bardisy, Mohammad Fawzy, Fang Cai, Nicole Soranzo, Adam Butterworth, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study (Italy), Mount Sinai Clinical Intelligence Center, GEN-COVID consortium (Spain), GenOMICC Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, Daniel H Geschwind, Stephanie Arteaga, Alexis Stephens, Manish J Butte, Paul C Boutros, Takafumi N Yamaguchi, Shu Tao, Stefan Eng, Timothy Sanders, Paul J Tung, Michael E Broudy, Yu Pan, Alfredo Gonzalez, Nikhil Chavan, Ruth Johnson, Bogdan Pasaniuc, Brian Yaspan, Sandra Smieszek, Carlo Rivolta, Stephanie Bibert, Pierre-Yves Bochud, Maciej Dabrowski, Pawel Zawadzki, Mateusz Sypniewski, Elżbieta Kaja, Pajaree Chariyavilaskul, Voraphoj Nilaratanakul, Nattiya Hirankarn, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Katsushi Tokunaga, Masaya Sugiyama, Yosuke Kawai, Takanori Hasegawa, Tatsuhiko Naito, Ho Namkoong, Ryuya Edahiro, Akinori Kimura, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga, Yukinori Okada, Seiya Imoto, Satoru Miyano, Serghei Mangul, Malak S Abedalthagafi, Hugo Zeberg, Joseph J Grzymski, Nicole L Washington, Stephan Ossowski, Kerstin U Ludwig, Eva C Schulte, Olaf Riess, Marcin Moniuszko, Miroslaw Kwasniewski, Hamdi Mbarek, Said I Ismail, Anurag Verma, David B Goldstein, Krzysztof Kiryluk, Alessandra Renieri, Manuel A R Ferreira, and J Brent Richards

Subjects
Genetics, QH426-470
Abstract

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Published
2022
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4. Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlightsAPOL1as a high risk locus in patients with diabetic macular edema

Author

Amy D. Stockwell, Michael C. Chang, Anubha Mahajan, William Forrest, Neha Anegondi, RK Pendergrass, Suresh Selvaraj, Jens Reeder, Eric Wei, VA Iglesias, Natalie M. Creps, Laura Macri, Andrea N. Neeranjan, Marcel P. van der Brug, Suzie J. Scales, Mark I. McCarthy, and Brian L. Yaspan

Abstract

Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a multi-ancestry GWAS to assess DME risk in a total of 1,502 DME patients and 5,603 non-DME controls in discovery and replication datasets. Two loci reached GWAS significance (p−8). The strongest association was rs2239785, (K150E) inAPOL1. The second finding was rs10402468, which co-localized toPLVAPandANKLE1in vascular / endothelium tissues. We conducted multiple sensitivity analyses to establish that the associations were specific to DME status and did not reflect diabetes status or other diabetic complications. Here we report two novel loci for risk of DME which replicated in multiple clinical trial and biobank derived datasets. One of these loci, containing the geneAPOL1, is a risk factor in African American DME and DKD patients, indicating that this locus plays a broader role in diabetic complications for multiple ancestries.

Published
2023
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5. A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration

Author

Luz D. Orozco, Leah Owen, Jeffrey Hofmann, Amy D. Stockwell, Jianhua Tao, Susan Haller, Vineeth T. Mukundan, Christine Clarke, Jessica Lund, Akshayalakshmi Sridhar, Julie L. Barr, Rylee A. Zavala, Elijah C. Graves, Charles Zhang, Nadine Husami, Robert Finley, Elizabeth Au, John H. Lillvis, Michael H. Farkas, Akbar Shakoor, Richard M. Sherva, Ivana K. Kim, Joshua S. Kaminker, Michael J. Townsend, Lindsay A. Farrer, Brian L. Yaspan, Hsu-Hsin Chen, and Margaret M. DeAngelis

Subjects
macular degeneration, Age-related Macular Degeneration
Abstract

Age-related Macular Degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. We present a comprehensive molecular atlas for different stages of AMD.

Published
2022
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6. A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration

Author

Luz D. Orozco, Leah A. Owen, Jeffrey Hofmann, Amy D. Stockwell, Jianhua Tao, Susan Haller, Vineeth T. Mukundan, Christine Clarke, Jessica Lund, Akshayalakshmi Sridhar, Oleg Mayba, Julie L. Barr, Rylee A. Zavala, Elijah C. Graves, Charles Zhang, Nadine Husami, Robert Finley, Elizabeth Au, John H. Lillvis, Michael H. Farkas, Akbar Shakoor, Richard Sherva, Ivana K. Kim, Joshua S. Kaminker, Michael J. Townsend, Lindsay A. Farrer, Brian L. Yaspan, Hsu-Hsin Chen, and Margaret M. DeAngelis

Subjects
Genetics, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Published
2023
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7. Multi-ancestry GWAS analysis identifies two novel loci associated with diabetic eye disease and highlights APOL1 as a high risk locus in patients with diabetic macular edema.

Author

Amy D Stockwell, Michael C Chang, Anubha Mahajan, William Forrest, Neha Anegondi, Rion K Pendergrass, Suresh Selvaraj, Jens Reeder, Eric Wei, Victor A Iglesias, Natalie M Creps, Laura Macri, Andrea N Neeranjan, Marcel P van der Brug, Suzie J Scales, Mark I McCarthy, and Brian L Yaspan

Subjects
Genetics, QH426-470
Abstract

Diabetic retinopathy (DR) is a common complication of diabetes. Approximately 20% of DR patients have diabetic macular edema (DME) characterized by fluid leakage into the retina. There is a genetic component to DR and DME risk, but few replicable loci. Because not all DR cases have DME, we focused on DME to increase power, and conducted a multi-ancestry GWAS to assess DME risk in a total of 1,502 DME patients and 5,603 non-DME controls in discovery and replication datasets. Two loci reached GWAS significance (p

Published
2023
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