Phenotypic and Genetic Relationship between Brain Structure and Endogenous Sex-hormone Levels in UKB
Poster No:
848
Submission Type:
Abstract Submission
Authors:
Xochitl Diaz1, Santiago Daiz-Torres2, Xikun Han3, Adrian Campos4, Stuart MacGregor3, Jue Ong3, Miguel Renteria5
Institutions:
1Queenslan Institute of Medical Research, Brisbane, Queensland, 2QIMR Berghofer Medical Research Institute, Brisbane, QLD, 3Queenslan Institute of Medical Research, Brisbane, QLD, 4Regeneron Genetics Centre, Tarrytown, NY, 5Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute, Brisbane, AK
First Author:
Co-Author(s):
Miguel Renteria
Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute
Brisbane, AK
Mental Health & Neuroscience Program, QIMR Berghofer Medical Research Institute
Brisbane, AK
Introduction:
Sex hormones, including testosterone and sex hormone-binding-globulin (SHBG), are steroid hormones that play vital roles in sexual development, reproduction, and general health. Deficiencies have been linked to many age-related disorders such as cardiovascular disease, Parkinson's disease, Alzheimer's disease and diabetes.
In the present study, we leveraged structural neuroimaging and serum biochemistry data from up to 17,000 middle-aged participants in the UK Biobank. We interrogated sex-stratified cohorts to comprehensively map the phenotypic and genetic relationships between endogenous sex hormone levels and 74 brain morphometry phenotypes. We hypothesised that, for specific regions in the brain, differences in endogenous sex-hormone levels might contribute to variation in brain structure irrespective of sex and that the presence of sex differences on the genetic basis of brain structure may, in part, be explained by the sex-specific genetic influence of endogenous sex hormones.
In the present study, we leveraged structural neuroimaging and serum biochemistry data from up to 17,000 middle-aged participants in the UK Biobank. We interrogated sex-stratified cohorts to comprehensively map the phenotypic and genetic relationships between endogenous sex hormone levels and 74 brain morphometry phenotypes. We hypothesised that, for specific regions in the brain, differences in endogenous sex-hormone levels might contribute to variation in brain structure irrespective of sex and that the presence of sex differences on the genetic basis of brain structure may, in part, be explained by the sex-specific genetic influence of endogenous sex hormones.
Methods:
We screened all trait-pair associations between sex hormone level and brain morphometry phenotype. Our analysis can be summarised into three main steps:
Step 1: We performed cross-sectional multivariable linear regression analyses to evaluate the observational sex-specific association between neuroimaging phenotypes and endogenous sex hormone levels.
Step 2: We use a linear mixed model association implemented in BOLT-LMM and perform GWAS for each rank-transformed neuro-imaging phenotype by sex. Then, we estimated the genetic correlation (Gr) between sex hormone levels and brain morphology in both sexes via LD-score regression.
Step 3: Finally, we followed up correlated trait pairs with genetic causality analyses (e.g., Mendelian randomisation) to test for evidence of a potential causal (i.e., directional) relationship.
Step 1: We performed cross-sectional multivariable linear regression analyses to evaluate the observational sex-specific association between neuroimaging phenotypes and endogenous sex hormone levels.
Step 2: We use a linear mixed model association implemented in BOLT-LMM and perform GWAS for each rank-transformed neuro-imaging phenotype by sex. Then, we estimated the genetic correlation (Gr) between sex hormone levels and brain morphology in both sexes via LD-score regression.
Step 3: Finally, we followed up correlated trait pairs with genetic causality analyses (e.g., Mendelian randomisation) to test for evidence of a potential causal (i.e., directional) relationship.
Results:
Observational findings: We identified 15 associations between brain morphology traits and SHBG, with 13 associations shown in women and two associations in men. Notably, the surface area of the supramarginal gyrus was associated with differences in endogenous SHBG levels in both sexes. There were strong associations between testosterone phenotypes and thickness of paracentral and precentral (p=1e-4).
Genetic correlations: Except for six, all brain morphology traits had an estimated Gr above 0.8 between males and females, suggesting limited evidence for a sex difference in the genetic architecture of neuroimaging traits. Gr between brain morphology and sex hormone levels were modest (ranging from -0.13 to 0.16)[Figure 1]. Across both sexes, 6 out of 7 subcortical volume phenotypes were genetically correlated with SHBG levels: pallidum, thalamus, accumbens, caudate, amygdala and hippocampus. The surface area of the isthmus cingulate gyrus showed the strongest evidence of being genetically correlated with both freeT and totalT in females. Some brain traits were genetically associated with testosterone levels in the opposite direction, including the supramarginal and superior temporal gyri thickness.
Causal inference: Only the MR association between SHBG and the caudate nucleus volume in women and the association between SHBG and thickness of the pericalcarine in women showed consistent effect sizes across our association analyses. The strongest MR association was observed for genetically predicted SHBG on the subcortical volume of the putamen, although the phenotypic association was negligibly small.
Genetic correlations: Except for six, all brain morphology traits had an estimated Gr above 0.8 between males and females, suggesting limited evidence for a sex difference in the genetic architecture of neuroimaging traits. Gr between brain morphology and sex hormone levels were modest (ranging from -0.13 to 0.16)[Figure 1]. Across both sexes, 6 out of 7 subcortical volume phenotypes were genetically correlated with SHBG levels: pallidum, thalamus, accumbens, caudate, amygdala and hippocampus. The surface area of the isthmus cingulate gyrus showed the strongest evidence of being genetically correlated with both freeT and totalT in females. Some brain traits were genetically associated with testosterone levels in the opposite direction, including the supramarginal and superior temporal gyri thickness.
Causal inference: Only the MR association between SHBG and the caudate nucleus volume in women and the association between SHBG and thickness of the pericalcarine in women showed consistent effect sizes across our association analyses. The strongest MR association was observed for genetically predicted SHBG on the subcortical volume of the putamen, although the phenotypic association was negligibly small.
·Sex-stratified Gr estimates between endogenous sex hormones and brain morphology phenotypes.
Conclusions:
Although the robust phenotypic and genetic relationship between SHBG and cortical thickness in women confirms findings from previous studies, several novel findings, such as those between testosterone and the surface area of the lateral orbitofrontal cortex, warrant independent validation.
While we show that the pattern of Gr between sex hormones and morphology phenotypes might differ by sex, evidence of genetic causality between the two remains limited.
While we show that the pattern of Gr between sex hormones and morphology phenotypes might differ by sex, evidence of genetic causality between the two remains limited.
Genetics:
Genetic Association Studies 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping 2
Normal Development
Subcortical Structures
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
ADULTS
Blood
Computational Neuroscience
Cortex
Cortical Layers
MRI
Sexual Dimorphism
STRUCTURAL MRI
Sub-Cortical
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