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

doi:10.1038/s41398-021-01736-6

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

Human genetics

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Article number	613
Journal	Translational psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01736-6
Publication status	Published - 1 Dec 2021

Access to Document

10.1038/s41398-021-01736-6

Cite this

Bressler, J., Davies, G., Smith, A. V., Saba, Y., Bis, J. C., Jian, X., Hayward, C., Yanek, L., Smith, J. A., Mirza, S. S., Wang, R., Adams, H. H. H., Becker, D., Boerwinkle, E., Campbell, A., Cox, S. R., Eiriksdottir, G., Fawns-Ritchie, C., Gottesman, R. F., ... Deary, I. J. (2021). Association of low-frequency and rare coding variants with information processing speed. Translational psychiatry, 11(1), [613]. https://doi.org/10.1038/s41398-021-01736-6

@article{2d9c45543ff749b7943616e02434a86b,

title = "Association of low-frequency and rare coding variants with information processing speed",

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.",

author = "Jan Bressler and Gail Davies and Smith, {Albert V.} and Yasaman Saba and Bis, {Joshua C.} and Xueqiu Jian and Caroline Hayward and Lisa Yanek and Smith, {Jennifer A.} and Mirza, {Saira S.} and Ruiqi Wang and Adams, {Hieab H. H.} and Diane Becker and Eric Boerwinkle and Archie Campbell and Cox, {Simon R.} and Gudny Eiriksdottir and Chloe Fawns-Ritchie and Gottesman, {Rebecca F.} and Grove, {Megan L.} and Xiuqing Guo and Edith Hofer and Kardia, {Sharon L. R.} and Knol, {Maria J.} and Marisa Koini and Lopez, {Oscar L.} and Marioni, {Riccardo E.} and Paul Nyquist and Alison Pattie and Ozren Polasek and Porteous, {David J.} and Igor Rudan and Satizabal, {Claudia L.} and Helena Schmidt and Reinhold Schmidt and Stephen Sidney and Jeannette Simino and Smith, {Blair H.} and Turner, {Stephen T.} and {van der Lee}, {Sven J.} and Ware, {Erin B.} and Whitmer, {Rachel A.} and Kristine Yaffe and Qiong Yang and Wei Zhao and Vilmundur Gudnason and Launer, {Lenore J.} and Fitzpatrick, {Annette L.} and Psaty, {Bruce M.} and Myriam Fornage and {Arfan Ikram}, M. and {van Duijn}, {Cornelia M.} and Sudha Seshadri and Mosley, {Thomas H.} and Deary, {Ian J.}",

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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41398-021-01736-6",

language = "English",

volume = "11",

journal = "Translational psychiatry",

issn = "2158-3188",

number = "1",

}

Bressler, J, Davies, G, Smith, AV, Saba, Y, Bis, JC, Jian, X, Hayward, C, Yanek, L, Smith, JA, Mirza, SS, Wang, R, Adams, HHH, Becker, D, Boerwinkle, E, Campbell, A, Cox, SR, Eiriksdottir, G, Fawns-Ritchie, C, Gottesman, RF, Grove, ML, Guo, X, Hofer, E, Kardia, SLR, Knol, MJ, Koini, M, Lopez, OL, Marioni, RE, Nyquist, P, Pattie, A, Polasek, O, Porteous, DJ, Rudan, I, Satizabal, CL, Schmidt, H, Schmidt, R, Sidney, S, Simino, J, Smith, BH, Turner, ST, van der Lee, SJ, Ware, EB, Whitmer, RA, Yaffe, K, Yang, Q, Zhao, W, Gudnason, V, Launer, LJ, Fitzpatrick, AL, Psaty, BM, Fornage, M, Arfan Ikram, M, van Duijn, CM, Seshadri, S, Mosley, TH & Deary, IJ 2021, 'Association of low-frequency and rare coding variants with information processing speed', Translational psychiatry, vol. 11, no. 1, 613. https://doi.org/10.1038/s41398-021-01736-6

TY - JOUR

T1 - Association of low-frequency and rare coding variants with information processing speed

AU - Bressler, Jan

AU - Davies, Gail

AU - Smith, Albert V.

AU - Saba, Yasaman

AU - Bis, Joshua C.

AU - Jian, Xueqiu

AU - Hayward, Caroline

AU - Yanek, Lisa

AU - Smith, Jennifer A.

AU - Mirza, Saira S.

AU - Wang, Ruiqi

AU - Adams, Hieab H. H.

AU - Becker, Diane

AU - Boerwinkle, Eric

AU - Campbell, Archie

AU - Cox, Simon R.

AU - Eiriksdottir, Gudny

AU - Fawns-Ritchie, Chloe

AU - Gottesman, Rebecca F.

AU - Grove, Megan L.

AU - Guo, Xiuqing

AU - Hofer, Edith

AU - Kardia, Sharon L. R.

AU - Knol, Maria J.

AU - Koini, Marisa

AU - Lopez, Oscar L.

AU - Marioni, Riccardo E.

AU - Nyquist, Paul

AU - Pattie, Alison

AU - Polasek, Ozren

AU - Porteous, David J.

AU - Rudan, Igor

AU - Satizabal, Claudia L.

AU - Schmidt, Helena

AU - Schmidt, Reinhold

AU - Sidney, Stephen

AU - Simino, Jeannette

AU - Smith, Blair H.

AU - Turner, Stephen T.

AU - van der Lee, Sven J.

AU - Ware, Erin B.

AU - Whitmer, Rachel A.

AU - Yaffe, Kristine

AU - Yang, Qiong

AU - Zhao, Wei

AU - Gudnason, Vilmundur

AU - Launer, Lenore J.

AU - Fitzpatrick, Annette L.

AU - Psaty, Bruce M.

AU - Fornage, Myriam

AU - Arfan Ikram, M.

AU - van Duijn, Cornelia M.

AU - Seshadri, Sudha

AU - Mosley, Thomas H.

AU - Deary, Ian J.

N1 - 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).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85120892161&partnerID=8YFLogxK

U2 - 10.1038/s41398-021-01736-6

DO - 10.1038/s41398-021-01736-6

M3 - Article

C2 - 34864818

VL - 11

JO - Translational psychiatry

JF - Translational psychiatry

SN - 2158-3188

IS - 1

M1 - 613

ER -

Association of low-frequency and rare coding variants with information processing speed

Abstract

Access to Document

Other files and links

Cite this