Klotho gene polymorphism, brain structure and cognition in early-life development

Clarisse Florence de Vries, Roger Staff* (Corresponding Author), Kimberly G. Noble, Ryan L. Muetzel, Meike W. Vernooij, Tonya White, Gordon David Waiter, Alison Dorothy Murray

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Variation in the klotho gene is linked to differences in health outcomes: klotho allele KL-VS heterozygosity is associated with longevity, better cognition and greater right frontal grey matter volume in late life. Contradicting reports, however, suggest that KL-VS’s effect on health might be age-dependent. Here we examine the relationship between KL-VS genotype, cognition and brain structure in childhood and adolescence. We hypothesized that KL-VS has early influences on cognitive and brain development. We investigated the associations of KL-VS carrier status with cognition and brain morphology in a cohort of 1387 children and adolescents aged 3–21 years, examining main effects and interactions between age, sex and socioeconomic circumstance. KL-VS had no main effect on either cognition or brain structure, though there was a significant KL-VS × age interaction for cognition (specifically executive function, attention, episodic memory, and general cognition), total grey matter and total brain volume. KL-VS heterozygotes had better cognition than non-carriers before age 11, but lower cognition after age 11. Heterozygotes had smaller brains than non-carriers did in early childhood. Sex moderated the association between KL-VS and white matter volume. Among girls, KL-VS heterozygotes had smaller white matter volumes than non-carriers. Among boys, heterozygotes had greater white matter volumes than non-carriers. However, a replication in a cohort of 2306 children aged 6–12 years showed no significant associations. In contrast to findings in late life, these results show that KL-VS does not have a main effect on cognition and brain structure. Furthermore, KL-VS’s influence may depend on age and sex.
Original languageEnglish
Pages (from-to)213-225
Number of pages13
JournalBrain Imaging and Behavior
Early online date5 Nov 2018
Publication statusPublished - 1 Feb 2020

Bibliographical note

Open access via Springer Compact Agreement

We thank the PING study participants who contributed to the research. The study was supported by the University of Aberdeen Development Trust and by the SINAPSE (Scottish Imaging Network: A Platform for Scientific Excellence) Postdoctoral and Early Career Researcher Exchanges funding. The PING Study (National Institutes of Health Grant RC2DA029475) funded data collection and sharing for this project. PING is funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. PING data are disseminated by the PING Coordinating Center at the Center for Human Development, University of California, San Diego.

Data used in preparation of this article were obtained from the Pediatric Imaging, Neurocognition and Genetics Study (PING) database (http://ping.chd.ucsd.edu/). As such, the investigators within PING contributed to the design and implementation of PING and/or provided data but did not participate in analysis or writing of this report. A complete listing of PING investigators can be found at http://ping.chd.ucsd.edu/index.php?option=com_content&view=article&id=104&Itemid=134.

The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. Neuroimaging was supported by the Netherlands Organization for Health Research and Development (ZonMw) TOP project number 91211021. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. We would like to thank Karol Estrada, Dr. Tobias A. Knoch, Anis Abuseiris, Luc V. de Zeeuw, and Rob de Graaf, for their help in creating GRIMP, BigGRID, MediGRID, and Services@MediGRID/D-Grid, [funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015 G] for access to their grid computing resources. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Manoushka Ganesh, Lizbeth Herrera and Marjolein Peters for their help in creating, managing and QC of the GWAS database.

The general design of Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, ZonMw, the Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport and the Ministry of Youth and Families.


  • Klotho
  • Polymorphism
  • Development
  • Cognition
  • Brain


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