Translational Psychiatry (Dec 2021)
Association of low-frequency and rare coding variants with information processing speed
- Jan Bressler,
- Gail Davies,
- Albert V. Smith,
- Yasaman Saba,
- Joshua C. Bis,
- Xueqiu Jian,
- Caroline Hayward,
- Lisa Yanek,
- Jennifer A. Smith,
- Saira S. Mirza,
- Ruiqi Wang,
- Hieab H. H. Adams,
- Diane Becker,
- Eric Boerwinkle,
- Archie Campbell,
- Simon R. Cox,
- Gudny Eiriksdottir,
- Chloe Fawns-Ritchie,
- Rebecca F. Gottesman,
- Megan L. Grove,
- Xiuqing Guo,
- Edith Hofer,
- Sharon L. R. Kardia,
- Maria J. Knol,
- Marisa Koini,
- Oscar L. Lopez,
- Riccardo E. Marioni,
- Paul Nyquist,
- Alison Pattie,
- Ozren Polasek,
- David J. Porteous,
- Igor Rudan,
- Claudia L. Satizabal,
- Helena Schmidt,
- Reinhold Schmidt,
- Stephen Sidney,
- Jeannette Simino,
- Blair H. Smith,
- Stephen T. Turner,
- Sven J. van der Lee,
- Erin B. Ware,
- Rachel A. Whitmer,
- Kristine Yaffe,
- Qiong Yang,
- Wei Zhao,
- Vilmundur Gudnason,
- Lenore J. Launer,
- Annette L. Fitzpatrick,
- Bruce M. Psaty,
- Myriam Fornage,
- M. Arfan Ikram,
- Cornelia M. van Duijn,
- Sudha Seshadri,
- Thomas H. Mosley,
- Ian J. Deary
Affiliations
- Jan Bressler
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
- Gail Davies
- Lothian Birth Cohorts, University of Edinburgh
- Albert V. Smith
- Icelandic Heart Association
- Yasaman Saba
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz
- Joshua C. Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Xueqiu Jian
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston
- Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Lisa Yanek
- Department of General Internal Medicine, Johns Hopkins University School of Medicine
- Jennifer A. Smith
- Department of Epidemiology, School of Public Health, University of Michigan
- Saira S. Mirza
- Department of Epidemiology, Erasmus MC University Medical Center
- Ruiqi Wang
- Department of Biostatistics, Boston University School of Public Health
- Hieab H. H. Adams
- Department of Epidemiology, Erasmus MC University Medical Center
- Diane Becker
- Department of General Internal Medicine, Johns Hopkins University School of Medicine
- Eric Boerwinkle
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
- Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Simon R. Cox
- Lothian Birth Cohorts, University of Edinburgh
- Gudny Eiriksdottir
- Icelandic Heart Association
- Chloe Fawns-Ritchie
- Lothian Birth Cohorts, University of Edinburgh
- Rebecca F. Gottesman
- Department of Neurology, Johns Hopkins University School of Medicine
- Megan L. Grove
- Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston
- Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Edith Hofer
- Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz
- Sharon L. R. Kardia
- Department of Epidemiology, School of Public Health, University of Michigan
- Maria J. Knol
- Department of Psychology, University of Edinburgh
- Marisa Koini
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Oscar L. Lopez
- Department of Neurology, University of Pittsburgh School of Medicine
- Riccardo E. Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Paul Nyquist
- Department of Psychology, University of Edinburgh
- Alison Pattie
- Lothian Birth Cohorts, University of Edinburgh
- Ozren Polasek
- Faculty of Medicine, University of Split
- David J. Porteous
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Igor Rudan
- Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh
- Claudia L. Satizabal
- Framingham Heart Study
- Helena Schmidt
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz
- Reinhold Schmidt
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Stephen Sidney
- Kaiser Permanente Northern California Division of Research
- Jeannette Simino
- Department of Data Science, University of Mississippi Medical Center
- Blair H. Smith
- Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee
- Stephen T. Turner
- Division of Nephrology and Hypertension, Mayo Clinic
- Sven J. van der Lee
- Department of Psychology, University of Edinburgh
- Erin B. Ware
- Lothian Birth Cohorts, University of Edinburgh
- Rachel A. Whitmer
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Kristine Yaffe
- Department of Psychiatry, University of California San Francisco
- Qiong Yang
- Department of Biostatistics, Boston University School of Public Health
- Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan
- Vilmundur Gudnason
- Icelandic Heart Association
- Lenore J. Launer
- Laboratory of Epidemiology and Population Science, National Institute on Aging, Intramural Research Program, National Institutes of Health
- Annette L. Fitzpatrick
- Department of Family Medicine, University of Washington
- Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston
- M. Arfan Ikram
- Department of Psychology, University of Edinburgh
- Cornelia M. van Duijn
- Department of Epidemiology, Erasmus MC University Medical Center
- Sudha Seshadri
- Framingham Heart Study
- Thomas H. Mosley
- Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center
- Ian J. Deary
- Lothian Birth Cohorts, University of Edinburgh
- DOI
- https://doi.org/10.1038/s41398-021-01736-6
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 7
Abstract
Abstract Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
