Figure 9 - available via license: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
Content may be subject to copyright.
Effects of CACHD1 in hippocampal neurons. A, Colabeling of hippocampal neurons with CACHD1 and mVenus. B, CACHD1 increased the firing frequency of hippocampal neurons. C, Example traces representing depolarizing current injections steps of 20, 70, and 140 pA. D, Summary data from separate experiments confirming CACHD1-mediated increased firing frequency and also showing that TTA-P2 (1 M) reduced firing rates in CACHD1-expressing neurons, but not in controls. E, Rebound APs were evoked using a 50 pA hyperpolarizing prepulse followed by a depolarizing step from 0 to 200 pA in steps of 10 pA for 200 ms, CACHD1-expressing neurons displayed a significantly greater number of rebound APs compared with controls. F, Example traces representing depolarizing current injection steps of 40, 90 and 140 pA. G, Summary data from separate experiments confirming CACHD1-mediated increased in rebound APs and also showing that TTA-P2 (1 M) reduced firing rates in CACHD1-expressing neurons, but not in controls. *p 0.05 throughout, two-tailed paired Student's t test or one-way ANOVA with Bonferroni post hoc test. Figure 9 is supported by analysis of the effects of CACHD1 and TTA-P2 on biophysical properties of hippocampal neurons (Figure 9-1, available at https://doi.org/10.1523/JNEUROSCI.3572-15.2018.f9-1).
Source publication
The putative cache (Ca²⁺ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2δ voltage-gated Ca²⁺ channel auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus, and cerebellum, with a br...
Contexts in source publication
Context 1
... are predicted to affect neuronal excitability around the resting membrane potential ( Perez-Reyes, 2003;Cheong and Shin, 2013). To investigate the role of CACHD1 in controlling neuronal excitability, we expressed CACHD1 (vs empty vector controls) in hippocampal neurons. Transfected neurons were identified by coexpression of the biomarker mVenus ( Fig. 9A). At a depolarizing current injection step of 220 pA, CACHD1-expressing neurons fired at a higher frequency than control neurons ( Fig. 9 B, C,D; Table 2). To further determine the role of T-type currents in establishing the increase in neuronal firing frequencies, we used the selective Ca V 3 channel blocker TTA-P2 ( Dreyfus et al., ...
Context 2
... the role of CACHD1 in controlling neuronal excitability, we expressed CACHD1 (vs empty vector controls) in hippocampal neurons. Transfected neurons were identified by coexpression of the biomarker mVenus ( Fig. 9A). At a depolarizing current injection step of 220 pA, CACHD1-expressing neurons fired at a higher frequency than control neurons ( Fig. 9 B, C,D; Table 2). To further determine the role of T-type currents in establishing the increase in neuronal firing frequencies, we used the selective Ca V 3 channel blocker TTA-P2 ( Dreyfus et al., 2010). TTA-P2 (1 M) reversed the firing frequency in CACHD1-expressing neurons back to control levels, but was without effect on control neurons ( ...
Context 3
... 9 B, C,D; Table 2). To further determine the role of T-type currents in establishing the increase in neuronal firing frequencies, we used the selective Ca V 3 channel blocker TTA-P2 ( Dreyfus et al., 2010). TTA-P2 (1 M) reversed the firing frequency in CACHD1-expressing neurons back to control levels, but was without effect on control neurons ( Fig. 9D; Table 2). To increase the contribution of T-type current to neuronal excitability, a hyperpolarizing prepulse was used to recover LVA Ca 2 channels from inactivation, followed by a short depolarizing pulse to evoke an action potential (AP) ( Eckle et al., 2014). Under these conditions, CACHD1 expression caused a more profound increase ...
Context 4
... a hyperpolarizing prepulse was used to recover LVA Ca 2 channels from inactivation, followed by a short depolarizing pulse to evoke an action potential (AP) ( Eckle et al., 2014). Under these conditions, CACHD1 expression caused a more profound increase in rebound firing frequency in CACHD1-transfected neurons, but not in control neurons ( Fig. 9 E, F,G; Table 2). TTA-P2 (1 M) reversed the increase in rebound AP firing in CACHD1-expressing neurons back to control levels, but was without effect on control neurons ( Fig. 9G; Table 2). Throughout these experiments, CACHD1 had no significant effects on AP waveform properties ( Fig. 9-1, available at https:// ...
Context 5
... 2014). Under these conditions, CACHD1 expression caused a more profound increase in rebound firing frequency in CACHD1-transfected neurons, but not in control neurons ( Fig. 9 E, F,G; Table 2). TTA-P2 (1 M) reversed the increase in rebound AP firing in CACHD1-expressing neurons back to control levels, but was without effect on control neurons ( Fig. 9G; Table 2). Throughout these experiments, CACHD1 had no significant effects on AP waveform properties ( Fig. 9-1, available at https:// doi.org/10.1523/JNEUROSCI.3572-15.2018.f9-1). These data support a CACHD1-mediated selective increase in T-type Ca 2 current, which leads to an increase in AP firing frequency and excitability in native ...
Context 6
... in CACHD1-transfected neurons, but not in control neurons ( Fig. 9 E, F,G; Table 2). TTA-P2 (1 M) reversed the increase in rebound AP firing in CACHD1-expressing neurons back to control levels, but was without effect on control neurons ( Fig. 9G; Table 2). Throughout these experiments, CACHD1 had no significant effects on AP waveform properties ( Fig. 9-1, available at https:// doi.org/10.1523/JNEUROSCI.3572-15.2018.f9-1). These data support a CACHD1-mediated selective increase in T-type Ca 2 current, which leads to an increase in AP firing frequency and excitability in native ...
Context 7
... V 3.2 transcripts were upregulated in TLE models, and intrinsic burst firing was reduced in Ca V 3.2 knock-out mice (Becker et al., 2008). Moreover, the deubiquitinating enzyme Figure 9. Effects of CACHD1 in hippocampal neurons. ...
Context 8
... 0.05 throughout, two-tailed paired Student's t test or one-way ANOVA with Bonferroni post hoc test. Figure 9 is supported by analysis of the effects of CACHD1 and TTA-P2 on biophysical properties of hippocampal neurons ( USP5 ( García-Caballero et al., 2014) and the prevention of Ca V 3.2 deubiquitination were suggested to be beneficial in neuropathic and inflammatory pain. Our data suggest CACHD1 as a potential future target in hyperexcitability disorders associated with Ca V 3 dysfunction, such as epilepsy and pain. ...
Citations
... Therefore, HVA calcium channels consist of a principal functional pore-forming α1-subunit that associates with an α2δ dimer (disulfide-linked), an intracellular β-subunit (phosphorylated), and often a transmembrane γ-subunit (Curtis and Catterall 1984;Takahashi and Catterall 1987). It was recently demonstrated that CACHD1 is structurally an α2δlike protein that functionally modulates Ca v 3 activity (Cottrell et al. 2018). ...
In vertebrates, two types of ion channels are responsible for amplifying electrical signals and facilitating neurotransmission: voltage-gated sodium (Nav1) and calcium (Cav3) channels. When the cell membrane is moderately depolarized, these channels allow the rapid influx of their respective ions – Na+ and Ca2+. Nav1 and Cav3 channels are structurally related, and their expression overlaps in various excitable tissues, such as muscles and neurons. Dysfunction of these depolarization-activated cation channels can lead to various diseases including neuropathic pain, epilepsy, atrial fibrillation, and cancer. Hence, compounds that can modulate the function of both Nav1 and Cav3 channels have the potential to be used as therapeutic agents. This chapter will primarily focus on venom-derived peptide toxins and small molecules that dually affect Nav1 and Cav3 channels.
... Nevertheless, they all share a similar protein domain organisation, including important common structural properties (see Fig. 1). CACHD1 [cache (Ca 2+ channel and chemotaxis receptor) domain containing 1] protein was first identified to be related to α 2 δ auxiliary subunits by Cottrell et al. (2018) using bioinformatics approaches. Due to the similar structural properties, CACHD1 has been described as an α 2 δ-like protein (Cottrell et al. 2018) and is now broadly considered a member of the α 2 δ protein family. ...
... CACHD1 [cache (Ca 2+ channel and chemotaxis receptor) domain containing 1] protein was first identified to be related to α 2 δ auxiliary subunits by Cottrell et al. (2018) using bioinformatics approaches. Due to the similar structural properties, CACHD1 has been described as an α 2 δ-like protein (Cottrell et al. 2018) and is now broadly considered a member of the α 2 δ protein family. ...
... Due to its predicted structural similarities to members of the α 2 δ family, the CACHD1 protein was reported as an α 2 δ-like protein (Whittaker and Hynes 2002) and shown to functionally modulate calcium channel currents (T-type by Cottrell et al. (2018) and N-type by Dahimene et al. (2018)) ( Fig. 3) (Cottrell et al. 2018;Dahimene et al. 2018;Stephens and Cottrell 2019). Despite low sequence similarity (only a 13-16% gene homology and a < 21% protein identity) to α 2 δ proteins ( Fig. 1b), there are multiple structural similarities between CACHD1 and α 2 δ proteins (Cottrell et al. 2018). ...
α2δ proteins are well-established modulators of membrane expression and biophysical properties of voltage-gated calcium channels. Moreover, they are critical regulators of synapse formation and function and key players in transsynaptic signalling. The α2δ isoforms are highly glycosylated membrane-anchored proteins with distinct structural features, some of which are also observed in a human α2δ-like protein termed CACHD1. Accumulating evidence has underpinned the involvement of α2δ proteins in neurological and neurodevelopmental disorders, making them attractive novel therapeutic targets. Also, CACHD1, through its modulation of T-type currents, is an emerging potential drug target, particularly for epilepsy and pain. Furthermore, α2δ proteins are targets of the widely prescribed gabapentinoids. Among these, gabapentin and pregabalin, which have a high binding affinity for α2δ-1 and α2δ-2, have been administered particularly in the treatment of neuropathic pain conditions, epilepsy, and restless leg syndrome. Extensive efforts have been and are being made to understand the structure and functions of α2δ proteins and how they interact with synaptic proteins. This is ultimately helping to understand the contribution of the α2δ protein family to neurological and neurodevelopmental disorders and provides insight into potential novel treatment options.
... However, the validity of these interactions/regulations has been contested [10,95], leaving unclear the exact molecular mechanisms by which Ca v β and Ca v α 2 δ might modulate T-type channels. Instead, a recent study has unveiled CACHD1 (calcium channel and chemotaxis receptor (cache) domain containing protein 1) as a Ca v α 2 δ-like modulator of Ca v 3 channels [38,139]. Although CACHD1 does not exhibit significant sequence identity with traditional Ca v α 2 δ proteins, it possesses the characteristic VWA (von Willebrand Factor A) domain, along with a putative bacterial chemosensory-like cache domain found in Ca v α 2 δ. ...
T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.
... The α2δ-like cache domain containing 1 (CACHD1; MIM: 620144) protein forms a complex with and modulates the activity and expression of high-voltage-activated N-type (Ca v 2.2) and low-voltage-activated T-type (Ca v 3) channels. 5,6 High levels of CACHD1 mRNA and protein are present in the mammalian central nervous system, especially in the cerebellum, hippocampus, and thalamus. 5 At the tissue level, CACHD1 expression overlaps the distribution of α2δ-3 proteins and Ca v 3 subunits; at the subcellular level, this protein colocalizes with Ca v 2.2 and Ca v 3 channels at the cell surface. ...
... 5,6 High levels of CACHD1 mRNA and protein are present in the mammalian central nervous system, especially in the cerebellum, hippocampus, and thalamus. 5 At the tissue level, CACHD1 expression overlaps the distribution of α2δ-3 proteins and Ca v 3 subunits; at the subcellular level, this protein colocalizes with Ca v 2.2 and Ca v 3 channels at the cell surface. 5,6 Overexpression of CACHD1 significantly increases Ca v 2.2 and Ca v 3 current density and maximal conductance, and CACHD1 is thought to exert these physiological effects by increasing cell surface expression and reducing endocytosis of these N-and T-type channels. ...
... 5 At the tissue level, CACHD1 expression overlaps the distribution of α2δ-3 proteins and Ca v 3 subunits; at the subcellular level, this protein colocalizes with Ca v 2.2 and Ca v 3 channels at the cell surface. 5,6 Overexpression of CACHD1 significantly increases Ca v 2.2 and Ca v 3 current density and maximal conductance, and CACHD1 is thought to exert these physiological effects by increasing cell surface expression and reducing endocytosis of these N-and T-type channels. 5,6 Importantly, members of the α2δ protein family have putative roles in development and disease independent of VGCC modulation, suggesting that the same could be true for CACHD1. ...
... CACHD1 is a newly discovered protein that interacts with Wnt-receptors, acts as a potential calcium channel and chemotaxis receptor, and is elevated in the male mammalian central nervous system. It has been found to play important roles in regulating neurogenesis, neuronal identity, Notch signaling, and Alzheimer's disease [106][107][108][109]. ...
Simple Summary
This review is focused on the research recently published in the field of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), and steatohepatitis (NASH)-associated liver cancer. We aimed to highlight recent omics research on novel genetic and protein contributions to NAFLD/NASH to discuss the mainstream molecular pathways and novel candidate biomarkers and molecular targets in NAFLD/NASH. Special attention is paid to the role mTOR, as multifunctional orchestrator in NASH progression to HCC.
Abstract
Non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (NASH) are chronic hepatic conditions leading to hepatocellular carcinoma (HCC) development. According to the recent “multiple-parallel-hits hypothesis”, NASH could be caused by abnormal metabolism, accumulation of lipids, mitochondrial dysfunction, and oxidative and endoplasmic reticulum stresses and is found in obese and non-obese patients. Recent translational research studies have discovered new proteins and signaling pathways that are involved not only in the development of NAFLD but also in its progression to NASH, cirrhosis, and HCC. Nevertheless, the mechanisms of HCC developing from precancerous lesions have not yet been fully elucidated. Now, it is of particular importance to start research focusing on the discovery of novel molecular pathways that mediate alterations in glucose and lipid metabolism, which leads to the development of liver steatosis. The role of mTOR signaling in NASH progression to HCC has recently attracted attention. The goals of this review are (1) to highlight recent research on novel genetic and protein contributions to NAFLD/NASH; (2) to investigate how recent scientific findings might outline the process that causes NASH-associated HCC; and (3) to explore the reliable biomarkers/targets of NAFLD/NASH-associated hepatocarcinogenesis.
... Calcium/calcineurin-regulated NFAT1 is a key regulator of T cell activation, differentiation and development and in abT cells it is activated by engagement of the TCR (92). Our finding of higher CACHD1 and other ion channels in Vd1 T cells could also potentially explain the heightened sensitivity to ionomycin treatment by increasing the level of intracellular calcium (93). AhR is a ligand-activated transcription factor that operates in a cell-type specific manner and modulates tissue homeostasis in ab T cells (94). ...
Under non-pathological conditions, human γδ T cells represent a small fraction of CD3⁺ T cells in peripheral blood (1-10%). They constitute a unique subset of T lymphocytes that recognize stress ligands or non-peptide antigens through MHC-independent presentation. Major human γδ T cell subsets, Vδ1 and Vδ2, expand in response to microbial infection or malignancy, but possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that differences at the gene, phenotypic, and functional level would provide evidence that γδ T cell subpopulations belong to distinct lineages. Comparisons between each subset and the identification of the molecular determinants that underpin their differences has been hampered by experimental challenges in obtaining sufficient numbers of purified cells. By utilizing a stringent FACS-based isolation method, we compared highly purified human Vδ1 and Vδ2 cells in terms of phenotype, gene expression profile, and functional responses. We found distinct genetic and phenotypic signatures that define functional differences in γδ T cell populations. Differences in TCR components, repertoire, and responses to calcium-dependent pathways suggest that Vδ1 and Vδ2 T cells are different lineages. These findings will facilitate further investigation into the ligand specificity and unique role of Vδ1 and Vδ2 cells in early immune responses.
... In α 2 δ proteins, as in some prokaryotic proteins, these were found to be organized into double Cache domains (dCache_1), and in bacteria, they are involved in amino acid nutrient binding in chemoreceptors and other signal transduction proteins, leading to intracellular signaling [35,36]. Although these domains are widely found in bacteria and archaea, where they have well-studied roles in nutrient sensing, the only animal proteins in which these dCache domains have been identified are α 2 δ proteins ( Figure 1), and the novel α 2 δ-like protein Cachd1 [35], which is a transmembrane protein with some α 2 δ-like properties [33,37,38] A conserved structural motif including several key residues was found to be essential for amino acid binding in all these dCache_1 domains, including in the first dCache_1 domain in α 2 δ-1 [35]. This [35]. ...
In this hybrid review, we have first collected and reviewed available information on the structure and function of the enigmatic cache domains in α2δ proteins. These are organized into two double cache (dCache_1) domains, and they are present in all α2δ proteins. We have also included new data on the key function of these domains with respect to amino acid and gabapentinoid binding to the universal amino acid–binding pocket, which is present in α2δ-1 and α2δ-2. We have now identified the reason why α2δ-3 and α2δ-4 do not bind gabapentinoid drugs or amino acids with bulky side chains. In relation to this, we have determined that the bulky amino acids Tryptophan and Phenylalanine prevent gabapentin from inhibiting cell surface trafficking of α2δ-1. Together, these novel data shed further light on the importance of the cache domains in α2δ proteins.
... A putative cache (Ca 2+ channel and chemotaxis receptor) domain containing protein 1 (CACHD1) has been described as an α 2 δ-like protein, displaying structural similarities to members of the α 2 δ family and showing a wide expression in the CNS [22,23]. An expression study using rat and zebrafish illustrated that Cachd1 increases N-type calcium currents and surface expression and competes with α 2 δ-1 for binding to Ca V 2.2 [24]. ...
... An expression study using rat and zebrafish illustrated that Cachd1 increases N-type calcium currents and surface expression and competes with α 2 δ-1 for binding to Ca V 2.2 [24]. Interestingly, upon co-expression, human CACHD1 also increased cell-surface localization of the Ca V 3.1 T-type channel [22], although T-type channels are not known to interact with auxiliary β and α 2 δ subunits [1]. Furthermore, overexpression of CACHD1 in hippocampal neurons caused a pronounced increase in T-type current-mediated spike firing [23]. ...
... The α 2 δ-like protein Cachd1 is strongly expressed in multiple brain areas including the hippocampus, cerebellum, and thalamus [22]. In contrast, CNS expression of α 2 δ-4 is very low in the hippocampus [15,20]. ...
The α2δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α2δ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism. Although the α2δ-4 isoform is predominantly found in the retina with very little expression in the brain, it was recently linked to brain functions. In contrast, Cachd1, a novel α2δ-like protein, shows strong expression in brain, but its function in neurons is not yet known. Therefore, we aimed to investigate the presynaptic functions of α2δ-4 and Cachd1 by expressing individual proteins in cultured hippocampal neurons. Both α2δ-4 and Cachd1 are expressed in the presynaptic membrane and could rescue a severe synaptic defect present in triple knockout/knockdown neurons that lacked the α2δ-1-3 isoforms (α2δ TKO/KD). This observation suggests that presynaptic localization and the regulation of synapse formation in glutamatergic neurons is a general feature of α2δ proteins. In contrast to this redundant presynaptic function, α2δ-4 and Cachd1 differentially regulate the abundance of presynaptic calcium channels and the amplitude of presynaptic calcium transients. These functional differences may be caused by subtle isoform-specific differences in α1-α2δ protein–protein interactions, as revealed by structural homology modelling. Taken together, our study identifies both α2δ-4 and Cachd1 as presynaptic regulators of synapse formation, differentiation, and calcium channel functions that can at least partially compensate for the loss of α2δ-1-3. Moreover, we show that regulating glutamatergic synapse formation and differentiation is a critical and surprisingly redundant function of α2δ and Cachd1.
... Cav3.3 can interact with other proteins that can modulate its channel activity including calmodulin (Chemin et al., 2017), Galpha(q/11)-coupled muscarinic acetylcholine receptors (Hildebrand et al., 2007), and the α2δ-like Cache Domain-Containing 1 (CACHD1) protein (Cottrell et al., 2018). The location of the variants functionally tested in this study did not overlap with the known binding sites on Cav3.3 for any of these proteins, although it is possible that the variants may affect the Cav3.3 function via unknown binding sites for these proteins or other interacting proteins. ...
Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A, SCN1A, and ATP1A2, have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in CACNA1I may contribute to HM etiology.
... But across the literature, evaluation of sex differences in calcium channel functions and health consequences is limited. Several of the calcium channel sex-het genes appear to be annotated with sperm motility (CATSPER1) [27] conditions or be involved in increase in neuronal firing in male central nervous system (CACHD1) [28]. Surprisingly, we found sex-het SNP enrichment in fundamental proteins like the cytoskeletal proteins that play a wide range of functional and structural roles in human cells, such as transport, hormone secretion and synaptic transmission [29]. ...
Phenotypic differences across sexes are pervasive, but the genetic architecture of sex differences within and across phenotypes is mostly unknown. In this study, we aimed to improve detection power for sex-differentially contributing SNPs previously demonstrated to be enriched in disease association, and we investigate their functions in health, pathophysiology, and genetic function. We leveraged GIANT and UK Biobank summary statistics and defined a set of 2,320 independent SNPs having sexually dimorphic effects within and across biometric traits (MAF > 0.001, P < 5x10 ⁻⁸ ). Biometric trait sex-heterogeneous SNPs (sex-het SNPs) showed enrichment in association signals for 20 out of 33 diseases/traits at 5% alpha compared to sex-homogeneous matched SNPs ( empP < 0.001), and were significantly overrepresented in muscle, skeletal and stem cell development processes, and in calcium channel and microtubule complexes ( FDR < 0.05, empP < 0.05). Interestingly, we found that sex-het SNPs significantly map to predicted expression quantitative trait loci ( Pr-eQTLs ) across brain and other tissues, methylation quantitative trait loci ( meQTLs ) during development, and transcription start sites, compared to sex-homogeneous SNPs . Finally, we verified that the sex-het disease/trait enrichment was not explained by Pr-eQTL enrichment alone, as sex-het Pr-eQTLs were more enriched than matched sex-homogeneous Pr-eQTLs . We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk. These sex-het SNPs disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation. Together, our data emphasize the genetic underpinnings of sexual dimorphism and its role in human health.
