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Human Genetics

, Volume 134, Issue 1, pp 67–75 | Cite as

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores

  • Jonathon M. Davis
  • Veronica B. Searles
  • Nathan Anderson
  • Jonathon Keeney
  • Armin Raznahan
  • L. John Horwood
  • David M. Fergusson
  • Martin A. Kennedy
  • Jay Giedd
  • James M. Sikela
Original Investigation

Abstract

DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R 2 = 0.13, p = 0.02), which may be driven by males aged 6–11 (R 2 = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26–33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R 2 = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R 2 = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts.

Keywords

Brain Size North American Population DUF1220 Domain Total Gray Matter Volume Cognitive Aptitude 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Funding for this work was provided by NIH R01 MH081203 (JMS), Colorado Clinical and Translational Science Institute TL1 TR001081 (VBS), and a Graduate Assistantship from the Coleman Institute for Cognitive Disabilities (JK). CHDS was funded by Grants from the Health Research Council of New Zealand, the National Child Health Research Foundation, the Canterbury Medical Research Foundation, the New Zealand Lottery Grants Board, the Marsden Fund, and the James Hume Bequest Fund. We thank Allison Miller for preparation of DNA samples.

Conflict of interest

JMS is founder and shareholder of GATC Science, LLC, a biotech company focused on genomics.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jonathon M. Davis
    • 1
  • Veronica B. Searles
    • 1
  • Nathan Anderson
    • 1
  • Jonathon Keeney
    • 1
  • Armin Raznahan
    • 2
  • L. John Horwood
    • 3
  • David M. Fergusson
    • 3
  • Martin A. Kennedy
    • 4
  • Jay Giedd
    • 2
  • James M. Sikela
    • 1
  1. 1.Department of Biochemistry and Molecular Genetics and Human Medical Genetics, Medical Scientist Training and Neuroscience ProgramsUniversity of Colorado School of MedicineAuroraUSA
  2. 2.National Institute of Mental Health, Child Psychiatry BranchBethesdaUSA
  3. 3.Christchurch Health and Development Study, Department of Psychological MedicineUniversity of Otago, ChristchurchChristchurchNew Zealand
  4. 4.Department of Pathology, Gene Structure and Function LaboratoryUniversity of Otago, ChristchurchChristchurchNew Zealand

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