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The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7 , and with primary open-angle glaucoma (POAG) at CDKN2B - AS1, CAV1/CAV2, and SIX1/SIX6 . To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p  = 8.0 × 10 −8 ). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1 , CDKN2B - AS1, GAS7 , CAV1/CAV2 , and SIX1/SIX6 , revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.

[This corrects the article DOI: 10.3389/fnmol.2025.1469467.].

Externalizing and internalizing behavioral tendencies underlie many psychiatric and substance use disorders. These tendencies are associated with differences in temperament that emerge early in development via the interplay of genetic and environmental factors. To better understand the neurobiology of temperament, we have selectively bred rats for generations to produce two lines with highly divergent behavior: bred Low Responders (bLRs) are highly inhibited and anxious in novel environments, whereas bred High Responders (bHRs) are highly exploratory, sensation-seeking, and prone to drug-seeking behavior. Recently, we delineated these heritable differences by intercrossing bHRs and bLRs (F 0 -F 1 -F 2 ) to produce a heterogeneous F 2 sample with well-characterized lineage and behavior (exploratory locomotion, anxiety-like behavior, Pavlovian conditioning). The identified genetic loci encompassed variants that could influence behavior via many mechanisms, including proximal effects on gene expression. Here we measured gene expression in male and female F 0 s ( n  = 12 bHRs, 12 bLRs) and in a large sample of heterogeneous F 2 s ( n  = 250) using hippocampal RNA-Seq. This enabled triangulation of behavior with both genetic and functional genomic data to implicate specific genes and biological pathways. Our results show that bHR/bLR differential gene expression is robust, surpassing sex differences in expression, and predicts expression associated with F 2 behavior. In F 0 and F 2 samples, gene sets related to growth/proliferation are upregulated with bHR-like behavior, whereas gene sets related to mitochondrial function, oxidative stress, and microglial activation are upregulated with bLR-like behavior. Integrating our F 2 RNA-Seq data with previously-collected whole genome sequencing data identified genes with hippocampal expression correlated with proximal genetic variation ( cis -expression quantitative trait loci or cis -eQTLs). These cis -eQTLs successfully predict bHR/bLR differential gene expression based on F 0 genotype. Sixteen of these genes are associated with cis -eQTLs colocalized within loci we previously linked to behavior and are strong candidates for mediating the influence of genetic variation on behavioral temperament. Eight of these genes are related to bioenergetics. Convergence between our study and others targeting similar behavioral traits revealed five more genes consistently related to temperament. Overall, our results implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, thereby modulating vulnerability to psychiatric and addictive disorders.

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2 cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders. Competing Interest Statement The authors have declared no competing interest. Footnotes * Updates to figures and revision to manuscript text

Selectively-bred High Responder (bHR) and Low Responder (bLR) rats model the extreme externalizing and internalizing behavior accompanying many psychiatric disorders. To elucidate gene expression underlying these heritable behavioral differences, bHRs and bLRs (generation 37) were used to produce a F0-F1-F2 cross. We measured exploratory locomotion, anxiety-like behavior, and reward cue sensitivity (Pavlovian Conditioned Approach), and performed hippocampal RNA-Seq in male and female F0s (n=24) and F2s (n=250). Behaviors that diverged during selective breeding remained correlated in F2s, implying a shared genetic basis. F0 bHR/bLR differential expression was robust, surpassing differences associated with sex, and predicted expression patterns associated with F2 behavior. With bHR-like behavior, gene sets related to growth/proliferation were upregulated, whereas with bLR-like behavior, gene sets related to mitochondrial function, oxidative stress, and microglial activation were upregulated. This differential expression could be successfully predicted based on F0 genotype using cis-expression quantitative trait loci (cis-eQTLs) identified in the F2s. Colocalization of these cis-eQTLs with behavioral Quantitative Trait Loci pinpointed 16 differentially expressed genes that were strong candidates for mediating the influence of genetic variation on behavioral temperament. Our findings implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, modulating vulnerability to psychiatric disorders.

In humans, differences in temperament are highly predictive of classes of psychopathology classified as externalizing versus internalizing disorders. To better understand the genetic and neural causes of temperamental differences, we have selectively bred two lines of rats based on their exploration of a novel environment. The bred High Responder (bHR) and bred Low Responder (bLR) rats show contrasting heritable behaviors that map onto human temperamental differences and are associated with two paths to drug abuse: sensation seeking and reactivity to psychosocial stress. To elucidate the genes that underlie the divergent behavior of bHR/bLR rats, we created a bHR×bLR F0–F1–F2 cross and performed behavioral testing, transcriptional profiling, and genetic sequencing. We used RNA–Seq to characterize hippocampal tissue in F0s (n=24, n=6 per phenotype /sex) and F2s (n=250, n=125 per sex) to identify differentially expressed genes related to bHR/bLR lineage and phenotypical behaviors: locomotor response to novelty, anxiety, and Pavlovian Conditioned Approach (PavCA). We found that bHR/bLR phenotypical behaviors remained correlated in the F2s, implying a shared genetic basis. We also found robust differences in hippocampal transcriptional profiles associated with bHR/bLR lineage in the F0s which surpassed the differences associated with sex. These distinct expression profiles were predictive of gene expression patterns associated with F2 bHR/bLR behavior. We then prioritized bHR/bLR differentially expressed genes identified in our current and previous studies as candidates for mediating bHR/bLR phenotypical behaviors in F2s. Seventeen genes were differentially expressed in association with locomotor response to novelty, many of which also had nominal relationships with PavCA behavior. Seven of these genes were located near (±1MB) quantitative trait loci for bHR/bLR phenotypical behavior identified in our previous exome sequencing or genome wide association studies: AABR07071904, Ucp2, Ttc30a1, Fzd6, Spg7, Vps9d1, and Afg3l1. We also identified convergence between our model and other genetic rat models targeting internalizing behaviors, with 26 hippocampal genes showing shared patterns of differential expression, including Tmem144 and Mfge8. Our findings provide strong candidates for elucidating genetic and neurobiological factors that may shape differences in temperament and modulate vulnerability to psychiatric and addictive disorders. Competing Interest Statement The authors have declared no competing interest.

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

The complete array of genes required for terminal erythroid differentiation remains unknown. To address this knowledge gap, we perform a genome-scale CRISPR knock-out screen in the human erythroid progenitor cell line HUDEP-2 and validate candidate regulators of erythroid differentiation in a custom secondary screen. Comparison of sgRNA abundance in the CRISPR library, proerythroblasts, and orthochromatic erythroblasts, resulted in the identification of genes that are essential for proerythroblast survival and genes that are required for terminal erythroid differentiation. Among the top genes identified are known regulators of erythropoiesis, underscoring the validity of this screen. Notably, using a Log2 fold change of <−1 and false discovery rate of <0.01, the screen identified 277 genes that are required for terminal erythroid differentiation, including multiple genes not previously nominated through GWAS. NHLRC2 , which was previously implicated in hemolytic anemia, was a highly ranked gene. We suggest that anemia due to NHLRC2 mutation results at least in part from a defect in erythroid differentiation. Another highly ranked gene in the screen is VAC14 , which we validated for its requirement in erythropoiesis in vitro and in vivo. Thus, data from this CRISPR screen may help classify the underlying mechanisms that contribute to erythroid disorders. Using a genome-wide CRISPR knock-out screen, the authors defined the repertoire of genes that are required for proerythroblast survival and for terminal erythroid differentiation.