Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts

• Type of Material: Article
• Authors: Brooke G McKenna, Emory University; ongchao Huang, University of Iowa; Kévin Vervier, Wellcome Sanger Inst; Dabney Hofammann, University of Iowa; Mary Cafferata, University of Iowa; Seima Al-Momani, University of Nebraska, Omaha; Florencia Lowenthal, University of Iowa; Angela Zhang, University of Washington; Jin-Young Koh, University of Iowa; Savantha Thenuwara, Iowa State University; Leo Brueggeman, University of Iowa; Ethan Bahl, University of Iowa; Tanner Koomar, University of Iowa; Natalie Pottschmidt, Pennsylvania State University; Taylor Kalmus, University of Iowa; Lucas Casten, University of Iowa; Taylor R Thomas, University of Iowa; Jacob J Michaelson, University of Iowa
• Language: English
• Date: 2021-06-09
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13229-021-00450-w
• Title of Journal or Parent Work: MOLECULAR AUTISM
• Volume: 12
• Issue: 1
• Start Page: 43
• End Page: 43
• Grant/Funding Information: This work was supported by the National Institutes of Health [MH105527 and DC014489 to JJM]. This work was supported by a grant from the Simons Foundation (SFARI 516716, JJM). Author BGM was supported by the NSF Graduate Research Fellowship Program (DGE-1444932) during the completion of this work. This work was also supported by a grant to the University of Iowa Institution of Clinical and Translational Science, NIH and CTSA Grant Number: UL1TR002537.
• Keywords: Neurosciences; Neurosciences & Neurology; SEX-DIFFERENCES; Autism spectrum disorder; 2ND; AUTISM SPECTRUM DISORDER; DIGIT LENGTH; Androgen exposure; Social functioning; FINGER-LENGTH RATIOS; Masculinity; MALE-BRAIN THEORY; Neurodevelopment; Science & Technology; PSYCHOPATHOLOGY; FETAL TESTOSTERONE; ASSOCIATION; Life Sciences & Biomedicine; GIRLS; Genetics & Heredity
• Research Categories: Health Sciences, Public Health; Psychology, General

Abstract

Background: Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. Methods: Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. Results: We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all p< 0.05), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior (ρ= 0.19 , p= 0.004 ; ρ= 0.2 , p= 0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels (t= 4.0 , p= 8.8 × 10 - 5), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels (t= - 3.3 , p= 0.001). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning (t= - 2.3 , p= 0.02 , and t= 4.2 , p= 3.2 × 10 - 5 for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: - 0.22 ± 0.05 ; testosterone: - 0.35 ± 0.15 from 0.1%-ile to 99.9%-ile; SHBG: 0.64 ± 0.15 from 0.1%-ile to 99.9%-ile). Limitations: In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. Conclusions: These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.