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. GroveXiuqing 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

*Corresponding author for this work

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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.

Original languageEnglish
Article number613
JournalTranslational Psychiatry
Volume11
Issue number1
DOIs
Publication statusPublished - 4 Dec 2021

Bibliographical note

Funding Information:
Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant HL105756 and for the NeuroCHARGE phenotype working group through the National Institute on Aging grant AG033193. A full list of acknowledgements and details of grant support are provided in the Supplementary Information.

Publisher Copyright:
© 2021, The Author(s).

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