Altered pubertal timing in 7q11.23 copy number variations and associated genetic mechanisms.

Wei, Shau-Ming; Gregory, Michael D; Nash, Tiffany; de Abreu E Gouvêa, Andrea; Mervis, Carolyn B; Cole, Katherine M; Garvey, Madeline H; Kippenhan, J Shane; Eisenberg, Daniel P; Kolachana, Bhaskar; Schmidt, Peter J; Berman, Karen F

Wei, Shau-Ming; Gregory, Michael D; Nash, Tiffany; de Abreu E Gouvêa, Andrea; Mervis, Carolyn B; Cole, Katherine M; Garvey, Madeline H; Kippenhan, J Shane; Eisenberg, Daniel P; Kolachana, Bhaskar; Schmidt, Peter J; Berman, Karen F.

Afiliación

Wei SM; Behavioral Endocrinology Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Gregory MD; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Nash T; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
de Abreu E Gouvêa A; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Mervis CB; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Cole KM; Neurodevelopmental Sciences Laboratory, Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY, USA.
Garvey MH; Behavioral Endocrinology Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Kippenhan JS; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Eisenberg DP; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Kolachana B; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Schmidt PJ; Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Berman KF; Human Brain Collection Core, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.

iScience ; 27(3): 109113, 2024 Mar 15.

Article en En | MEDLINE | ID: mdl-38375233

ABSTRACT

ABSTRACT

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, Î·2 = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10-5, Î·p2 = 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.

Palabras clave

Genetics; Genotyping; Human Genetics

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