Altered pubertal timing in 7q11.23 copy number variations and associated genetic mechanisms
Shau-Ming Wei,
Michael D. Gregory,
Tiffany Nash,
Andrea de Abreu e Gouvêa,
Carolyn B. Mervis,
Katherine M. Cole,
Madeline H. Garvey,
J. Shane Kippenhan,
Daniel P. Eisenberg,
Bhaskar Kolachana,
Peter J. Schmidt,
Karen F. Berman
Affiliations
Shau-Ming Wei
Behavioral Endocrinology Branch, University of Louisville, Louisville, KY, USA; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Michael D. Gregory
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Tiffany Nash
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Andrea de Abreu e Gouvêa
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Carolyn B. Mervis
Neurodevelopmental Sciences Laboratory, Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY, USA
Katherine M. Cole
Behavioral Endocrinology Branch, University of Louisville, Louisville, KY, USA; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Madeline H. Garvey
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
J. Shane Kippenhan
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Daniel P. Eisenberg
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA
Bhaskar Kolachana
Human Brain Collection Core, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA
Peter J. Schmidt
Behavioral Endocrinology Branch, University of Louisville, Louisville, KY, USA
Karen F. Berman
Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, University of Louisville, Louisville, KY, USA; Corresponding author
Summary: Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R2 = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS < TD < Dup7; p = 1.2x10−8, η2 = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10−5, ηp2 = 0.2) with greater effect sizes. Finally, we relate an AAM-GWAS signal in 7q11.23 to altered expression in postmortem brains of STAG3L2 (p = 1.7x10−17), a gene we also find differentially expressed with 7q11.23 copy number (p = 0.03). Collectively, these data explicate the role of 7q11.23 in pubertal onset, with STAG3L2 and pituitary development as potential mediators.
