Pleiotropic Research Articles

A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity.

Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74-2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.

Major depression disorder may causally associate with the increased atrial fibrillation risk: evidence from two-sample mendelian randomization analyses

BackgroundObservational studies have revealed a link between major depressive disorder (MDD) and a higher chance of developing atrial fibrillation (AF). It is still uncertain whether or not this correlation indicates a causal relationship. This research set out to evaluate the causal impact of MDD on AF.MethodsTo evaluate the causal relationship between MDD and AF, we employed a two-sample Mendelian randomization (MR) method. A new genome-wide association study (GWAS) with 500,199 participants was used to obtain an overview of the association of genetic variations with MDD. An additional GWAS incorporating 1,030,836 people provided data on the relationship between gene variants and AF. The inverse-variance weighted technique was utilized to assess the effect sizes. Sensitivity analysis included the use of other statistical approaches such as weighted median, Outlier, MR Pleiotropy Residual Sum, weighted mode, simple mode, and MR - Egger.ResultsBy employing 47 single nucleotide polymorphisms (SNPs) as markers, MR analyses in random-effect inverse-variance weighted models found that genetically projected MDD was linked to an elevated incidence of AF (odds ratio [OR] = 1.098, 95% CI 1.000–1.206; P = 0.049). No gene pleiotropy was discovered as indicated by MR-Egger (intercept= -0.011, P = 0.169). Sensitivity analysis employing other MR techniques yielded reliable results.ConclusionThis MR study established a causal relationship between genetically predicted MDD and an elevated risk of AF.

Serine protease NAL1 exerts pleiotropic functions through degradation of TOPLESS-related corepressor in rice.

NARROW LEAF 1 (NAL1) is a breeding-valuable pleiotropic gene that affects multiple agronomic traits in rice, although the molecular mechanism is largely unclear. Here, we report that NAL1 is a serine protease and displays a novel hexameric structure consisting of two ATP-mediated doughnut-shaped trimeric complexes. Moreover, we identified TOPLESS-related corepressor OsTPR2 involved in multiple growth and development processes as the substrate of NAL1. We found that NAL1 degraded OsTPR2, thus modulating the expression of downstream genes related to hormone signalling pathways, eventually achieving its pleiotropic physiological function. An elite allele, NAL1A, which may have originated from wild rice, could increase grain yield. Furthermore, the NAL1 homologues in different crops have a similar pleiotropic function to NAL1. Our study uncovers a NAL1-OsTPR2 regulatory module and provides gene resources for the design of high-yield crops.

Identifying Genetic Architecture of Carcass and Meat Quality Traits in a Ningxiang Indigenous Pig Population.

Ningxiang pig is a breed renowned for its exceptional meat quality, but it possesses suboptimal carcass traits. To elucidate the genetic architecture of meat quality and carcass traits in Ningxiang pigs, we assessed heritability and executed a genome-wide association study (GWAS) concerning carcass length, backfat thickness, meat color parameters (L.LD, a.LD, b.LD), and pH at two postmortem intervals (45 min and 24 h) within a Ningxiang pig population. Heritability estimates ranged from moderate to high (0.30~0.80) for carcass traits and from low to high (0.11~0.48) for meat quality traits. We identified 21 significant SNPs, the majority of which were situated within previously documented QTL regions. Furthermore, the GRM4 gene emerged as a pleiotropic gene that correlated with carcass length and backfat thickness. The ADGRF1, FKBP5, and PRIM2 genes were associated with carcass length, while the NIPBL gene was linked to backfat thickness. These genes hold the potential for use in selective breeding programs targeting carcass traits in Ningxiang pigs.

Genetic variation analysis of pleiotropic gene Ghd7 in rice

Genetic variation analysis of pleiotropic gene Ghd7 in rice

Investigating the shared genetic architecture of post-traumatic stress disorder and gastrointestinal tract disorders: a genome-wide cross-trait analysis.

Observational studies suggest a correlation between post-traumatic stress disorder (PTSD) and gastrointestinal tract (GIT) disorders. However, the genetic overlap, causal relationships, and underlining mechanisms between PTSD and GIT disorders were absent. We obtained genome-wide association study statistics for PTSD (23 212 cases, 151 447 controls), peptic ulcer disease (PUD; 16 666 cases, 439 661 controls), gastroesophageal reflux disease (GORD; 54 854 cases, 401 473 controls), PUD and/or GORD and/or medications (PGM; 90 175 cases, 366 152 controls), irritable bowel syndrome (IBS; 28 518 cases, 426 803 controls), and inflammatory bowel disease (IBD; 7045 cases, 449 282 controls). We quantified genetic correlations, identified pleiotropic loci, and performed multi-marker analysis of genomic annotation, fast gene-based association analysis, transcriptome-wide association study analysis, and bidirectional Mendelian randomization analysis. PTSD globally correlates with PUD (rg = 0.526, p = 9.355 × 10-7), GORD (rg = 0.398, p = 5.223 × 10-9), PGM (rg = 0.524, p = 1.251 × 10-15), and IBS (rg = 0.419, p = 8.825 × 10-6). Cross-trait meta-analyses identify seven genome-wide significant loci between PTSD and PGM (rs13107325, rs1632855, rs1800628, rs2188100, rs3129953, rs6973700, and rs73154693); three between PTSD and GORD (rs13107325, rs1632855, and rs3132450); one between PTSD and IBS/IBD (rs4937872 and rs114969413, respectively). Proximal pleiotropic genes are mainly enriched in immune response regulatory pathways, and in brain, digestive, and immune systems. Gene-level analyses identify five candidates: ABT1, BTN3A2, HIST1H3J, ZKSCAN4, and ZKSCAN8. We found significant causal effects of GORD, PGM, IBS, and IBD on PTSD. We observed no reverse causality of PTSD with GIT disorders, except for GORD. PTSD and GIT disorders share common genetic architectures. Our work offers insights into the biological mechanisms, and provides genetic basis for translational research studies.

Inflammatory bowel disease increases the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian randomization analysis of European and East Asian populations.

Both inflammatory bowel disease (IBD) and hepato-pancreato-biliary cancers (HPBC) have been established to cause a huge socioeconomic burden. Epidemiological studies have revealed a close association between IBD and HPBC. Herein, we utilized inverse-variance weighting to conduct a two-sample Mendelian randomization analysis. We sought to investigate the link between various subtypes of IBD and HPBC. To ensure the accuracy and consistency of our findings, we conducted heterogeneity tests, gene pleiotropy tests, and sensitivity analyses. Compared to the general population, IBD patients in Europe exhibited a 1.22-fold increased incidence of pancreatic cancer (PC) with a 95% confidence interval (CI) of 1.0022-1.4888 (p = 0.0475). We also found a 1.14-fold increased incidence of PC in Crohn's disease (CD) patients with (95% CI: 1.0017-1.3073, p = 0.0472). In the East Asian population, the incidence of hepatocellular carcinoma (HCC) was 1.28-fold higher (95% CI = 1.0709-1.5244, p = 0.0065) in IBD patients than in the general population. Additionally, ulcerative colitis (UC) patients displayed 1.12-fold (95% CI: 1.1466-1.3334, p < 0.0001) and 1.31-fold (95% CI: 1.0983-1.5641, p = 0.0027) increased incidences of HCC and cholangiocarcinoma (CCA), respectively. Finally, the incidence of PC was 1.19-fold higher in CD patients than in the general population (95% CI = 1.0741-1.3132, p = 0.0008). Our study validated that IBD is a risk factor for HPBC. This causal relationship exhibited significant heterogeneity in different European and East Asian populations.

The causal effect of serum 25-hydroxyvitamin D levels on epilepsy: A two-sample Mendelian randomization study.

Observational studies have shown an association between 25-hydroxyvitamin D (25(OH)D) and epilepsy, but it is unclear whether the association is causal. Therefore, we applied Mendelian randomization (MR) analysis to determine the causal relationship between serum 25(OH)D levels and epilepsy. We conducted a two-sample Mendelian randomization (TSMR) study to investigate the association between serum 25(OH)D levels and epilepsy using pooled statistics from genome-wide association studies (GWAS). Data for 25(OH)D came from a GWAS comprising 417,580 participants, and data for epilepsy were obtained from the International League Against Epilepsy (ILAE) consortium. Five methods were used to analyze TSMR, including the inverse variance weighting method, MR Egger method, weighted median method, simple model, and weighted model. In the sensitivity analysis, MR Egger and MR PRESSO methods were used to test for pleiotropy, inverse variance weighting and MR Egger in Cochran's Q statistics were used to test for heterogeneity. MR analyzed the relationship between 25(OH)D and different types of epilepsy, and the results showed that a 1 standard deviation increase in natural log-transformed serum 25(OH)D levels was associated with reduced risk for juvenile absence epilepsy (IVW OR = 0.985; 95% confidence interval (CI): 0.971-0.999; P-value = 0.038). There was no apparent heterogeneity and horizontal gene pleiotropy. Higher serum levels of 25(OH)D were a protective factor for adolescent absence epilepsy, but had no effect on other types of epilepsy.

The AP2/ERF transcription factor TOE4b regulates photoperiodic flowering and grain yield per plant in soybean.

Photoperiod-mediated flowering determines the phenological adaptability of crops including soybean (Glycine max). A genome-wide association study (GWAS) identified a new flowering time locus, Time of flowering 13 (Tof13), which defined a gene encoding an AP2/ERF transcription factor. This new transcription factor, which we named TOE4b, is localized in the nucleus. TOE4b has been selected for soybean latitude adaptability. The existing natural variant TOE4bH4 was rare in wild soybean accessions but occurred more frequently in landraces and cultivars. Notably, TOE4bH4 improved high-latitude adaptation of soybean to some extent. The gene-edited TOE4b knockout mutant exhibited earlier flowering, conversely, TOE4b overexpression delayed flowering time. TOE4b is directly bound to the promoters and gene bodies of the key flowering integration factor genes FT2a and FT5a to inhibit their transcription. Importantly, TOE4b overexpression lines in field trials not only showed late flowering but also altered plant architecture, including shorter internode length, more internodes, more branches and pod number per plant, and finally boosted grain yield per plant by 60% in Guangzhou and 87% in Shijiazhuang. Our findings therefore identified TOE4b as a pleiotropic gene to increase yield potential per plant in soybean, and these results provide a promising option for breeding a soybean variety with an idealized plant architecture that promotes high yields.

Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.

Novel implication of the prolactin (PRL) gene in the comorbidity of type 2 diabetes and depression.

The prolactin (PRL) system plays important behavioral, social, and metabolic roles, such as mediating social bonding and insulin secretion. Inherited dysfunction of the PRL pathway-related genes is associated with psychopathology and insulin resistance. We have previously suggested that the PRL system might be implicated in the comorbidity of psychiatric (depression) and type 2 diabetes (T2D) owing to the pleiotropy of PRL pathway-related genes. To our knowledge, no PRL variants have so far been reported in patients with either major depressive disorder (MDD) and/or T2D. In this study, we analyzed 6 variants within the PRL gene and tested them for the presence of parametric linkage and/or linkage disequilibrium (LD, i.e., linkage and association) with familial MDD, T2D, and their comorbidity. We found, for the first time, that the PRL gene and its novel risk variants are linked to and in LD (i.e., linkage and association) with familial MDD, T2D, and MDD-T2D comorbidity. PRL might play a key role in mental-metabolic comorbidity and can be considered a novel gene in MDD and T2D.

Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases

Genetic correlation (r_g) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global r_g analyses show minimal r_g among neurodegenerative and neuropsychiatric diseases. Importantly, local r_g s can exist in the absence of global relationships. To investigate this possibility, we applied LAVA, a tool for local r_g analysis, to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer’s disease, Lewy body dementia and Parkinson’s disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several local r_g s missed in global analyses, including between (i) all 3 neurodegenerative diseases and schizophrenia and (ii) Alzheimer’s and Parkinson’s disease. For those local r_g s identified in genomic regions containing disease-implicated genes, such as SNCA, CLU and APOE, incorporation of expression quantitative trait loci identified genes that may drive genetic overlaps between diseases. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes. These findings imply sharing of pathogenic processes and the potential existence of common therapeutic targets.

25(OH)Vitamin D and autism spectrum disorder: genetic overlap and causality

ObjectiveTo identify whether there exists a genetic correlation and causal relationship between 25(OH)D and autism spectrum disorder (ASD).MethodsBased on large-scale genome-wide association studies, a series of genetic approaches were adopted to obtain summary statistics. Using linkage disequilibrium score regression, we assessed the shared polygenic structure between traits and performed pleiotropic analysis under composite null hypothesis (PLACO) to identify pleiotropic loci between complex traits. A bidirectional Mendelian randomization (MR) analysis was applied to investigate whether there is a causal relationship between 25(OH)D and ASD.ResultsThe linkage disequilibrium score regression (LDSC) showed a negative genetic correlation between 25(OH)D and ASD (rg = − 0.227, P < 0.05), and PLACO analysis identified 20 independent pleiotropic loci matched to 24 pleiotropic genes, of which the function reveals an underlying mechanism on 25(OH)D and ASD. In Mendelian randomization analysis, the inverse variance-weighted (IVW) method with OR = 0.941 (0.796, 1.112) and p < 0.474 did not show a causal relationship between 25(OH)D and ASD, while, in the reverse Mendelian randomization analysis, IVW method showed OR = 1.042 (0.930, 1.169), indicating no causal relationship either.ConclusionThis study provides evidence for a shared genetic overlap between 25(OH)D and ASD. Bidirectional MR analysis also did not show a definite causal relationship between 25(OH)D and ASD.

Pleiotropic loci for cannabis use disorder severity in multi-ancestry high-risk populations

Cannabis use disorder (CUD) is common and has in part a genetic basis. The risk factors underlying its development likely involve multiple genes that are polygenetic and interact with each other and the environment to ultimately lead to the disorder. Co-morbidity and genetic correlations have been identified between CUD and other disorders and traits in select populations primarily of European descent. If two or more traits, such as CUD and another disorder, are affected by the same genetic locus, they are said to be pleiotropic. The present study aimed to identify specific pleiotropic loci for the severity level of CUD in three high-risk population cohorts: American Indians (AI), Mexican Americans (MA), and European Americans (EA). Using a previously developed computational method based on a machine learning technique, we leveraged the entire GWAS catalog and identified 114, 119, and 165 potentially pleiotropic variants for CUD severity in AI, MA, and EA respectively. Ten pleiotropic loci were shared between the cohorts although the exact variants from each cohort differed. While majority of the pleiotropic genes were distinct in each cohort, they converged on numerous enriched biological pathways. The gene ontology terms associated with the pleiotropic genes were predominately related to synaptic functions and neurodevelopment. Notable pathways included Wnt/β-catenin signaling, lipoprotein assembly, response to UV radiation, and components of the complement system. The pleiotropic genes were the most significantly differentially expressed in frontal cortex and coronary artery, up-regulated in adipose tissue, and down-regulated in testis, prostate, and ovary. They were significantly up-regulated in most brain tissues but were down-regulated in the cerebellum and hypothalamus. Our study is the first to attempt a large-scale pleiotropy detection scan for CUD severity. Our findings suggest that the different population cohorts may have distinct genetic factors for CUD, however they share pleiotropic genes from underlying pathways related to Alzheimer's disease, neuroplasticity, immune response, and reproductive endocrine systems.

Pleiotropy promotes the evolution of inducible immune responses in a model of host-pathogen coevolution.

Components of immune systems face significant selective pressure to efficiently use organismal resources, mitigate infection, and resist parasitic manipulation. A theoretically optimal immune defense balances investment in constitutive and inducible immune components depending on the kinds of parasites encountered, but genetic and dynamic constraints can force deviation away from theoretical optima. One such potential constraint is pleiotropy, the phenomenon where a single gene affects multiple phenotypes. Although pleiotropy can prevent or dramatically slow adaptive evolution, it is prevalent in the signaling networks that compose metazoan immune systems. We hypothesized that pleiotropy is maintained in immune signaling networks despite slowed adaptive evolution because it provides some other advantage, such as forcing network evolution to compensate in ways that increase host fitness during infection. To study the effects of pleiotropy on the evolution of immune signaling networks, we used an agent-based modeling approach to evolve a population of host immune systems infected by simultaneously co-evolving parasites. Four kinds of pleiotropic restrictions on evolvability were incorporated into the networks, and their evolutionary outcomes were compared to, and competed against, non-pleiotropic networks. As the networks evolved, we tracked several metrics of immune network complexity, relative investment in inducible and constitutive defenses, and features associated with the winners and losers of competitive simulations. Our results suggest non-pleiotropic networks evolve to deploy highly constitutive immune responses regardless of parasite prevalence, but some implementations of pleiotropy favor the evolution of highly inducible immunity. These inducible pleiotropic networks are no less fit than non-pleiotropic networks and can out-compete non-pleiotropic networks in competitive simulations. These provide a theoretical explanation for the prevalence of pleiotropic genes in immune systems and highlight a mechanism that could facilitate the evolution of inducible immune responses.

Interaction between mutation type and gene pleiotropy drives parallel evolution in the laboratory.

What causes evolution to be repeatable is a fundamental question in evolutionary biology. Pleiotropy, i.e. the effect of an allele on multiple traits, is thought to enhance repeatability by constraining the number of available beneficial mutations. Additionally, pleiotropy may promote repeatability by allowing large fitness benefits of single mutations via adaptive combinations of phenotypic effects. Yet, this latter evolutionary potential may be reaped solely by specific types of mutations able to realize optimal combinations of phenotypic effects while avoiding the costs of pleiotropy. Here, we address the interaction of gene pleiotropy and mutation type on evolutionary repeatability in a meta-analysis of experimental evolution studies with Escherichia coli. We hypothesize that single nucleotide polymorphisms (SNPs) are principally able to yield large fitness benefits by targeting highly pleiotropic genes, whereas indels and structural variants (SVs) provide smaller benefits and are restricted to genes with lower pleiotropy. By using gene connectivity as proxy for pleiotropy, we show that non-disruptive SNPs in highly pleiotropic genes yield the largest fitness benefits, since they contribute more to parallel evolution, especially in large populations, than inactivating SNPs, indels and SVs. Our findings underscore the importance of considering genetic architecture together with mutation type for understanding evolutionary repeatability. This article is part of the theme issue 'Interdisciplinary approaches to predicting evolutionary biology'.

Interdisciplinary approaches to predicting evolutionary biology.

Interdisciplinary approaches to predicting evolutionary biology.

Maternal and fetal origins of offspring blood pressure: statistical analysis using genetic correlation and genetic risk score-based Mendelian randomization.

Epidemiological studies demonstrated that adverse in utero environment was associated with increased risk of offspring high blood pressure, by using birthweight as the proxy of maternal intrauterine exposure; however, the nature of such association remains less understood. With maternal/fetal-specific summary statistics of birthweight (n = 297 356 for own birthweight and n = 210 248 for offspring birthweight) and summary statistics of blood pressure [i.e. systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP)] (n = 757 601), we evaluated the genetic correlation between fetal-specific birthweight and blood pressure using cross-trait linkage disequilibrium score regression, and next detected pleiotropic genes for them with a pleiotropy mapping method called mixture-adjusted intersect-union pleiotropy test. Furthermore, we conducted a genetic risk score (GRS)-based Mendelian randomization analysis in parent-offspring pairs (n = 6031) of the UK Biobank cohort, to assess the causal relation between maternal-specific GRS and blood pressure conditioning on fetal genotypes. We found fetal-specific birthweight had a negative genetic correlation with DBP (ρ^g = -0.174, P = 1.68 × 10-10), SBP (ρ^g = -0.198, P = 8.09 × 10-12), and PP (ρ^g = -0.152, P = 6.04 × 10-8), and detected 143, 137 and 135 pleiotropic genes shared between fetal-specific birthweight and PP, SBP and DBP, respectively. These genes often exhibited opposite genetic effects, and were more likely to be differentially expressed in pancreas, liver, heart, brain, whole blood and muscle skeletal tissues. A causal negative association of maternal-specific birthweight was identified with SBP (P = 2.20 × 10-2) and PP (P = 7.67 × 10-3) but not DBP (P = 0.396) in mother-offspring pairs, after accounting for the influence of fetal-specific GRS; and the two significant relations were robust against the horizontal pleiotropy of instruments and the confounding influence of gestational duration and preterm birth. However, these causal associations could not be detected in father-offspring pairs. This study revealed common genetic components underlying birthweight and blood pressure, and provided important insight into aetiology and early prevention of high blood pressure.

Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders

Age-related macular degeneration (AMD), cataract, and glaucoma are leading causes of blindness worldwide. Previous genome-wide association studies (GWASs) have revealed a variety of susceptible loci associated with age-related ocular disorders, yet the genetic pleiotropy and causal genes across these diseases remain poorly understood. By leveraging large-scale genetic and observational data from ocular disease GWASs and UK Biobank (UKBB), we found significant pairwise genetic correlations and consistent epidemiological associations among these ocular disorders. Cross-disease meta-analysis uncovered seven pleiotropic loci, three of which were replicated in an additional cohort. Integration of variants in pleiotropic loci and multiple single-cell omics data identified that Müller cells and astrocytes were likely trait-related cell types underlying ocular comorbidity. In addition, we comprehensively integrated eye-specific gene expression quantitative loci (eQTLs), epigenomic profiling, and 3D genome data to prioritize causal pleiotropic genes. We found that pleiotropic genes were essential in nerve development and eye pigmentation, and targetable by aflibercept and pilocarpine for the treatment of AMD and glaucoma. These findings will not only facilitate the mechanistic research of ocular comorbidities but also benefit the therapeutic optimization of age-related ocular diseases.

The Effect of Developmental Pleiotropy on the Evolution of Insect Immune Genes.

The pressure to survive ever-changing pathogen exposure explains the frequent observation that immune genes are among the fastest evolving in the genomes of many taxa, but an intriguing proportion of immune genes also appear to be under purifying selection. Though variance in evolutionary signatures of immune genes is often attributed to differences in gene-specific interactions with microbes, this explanation neglects the possibility that immune genes participate in other biological processes that could pleiotropically constrain adaptive selection. In this study, we analyzed available transcriptomic and genomic data from Drosophila melanogaster and related species to test the hypothesis that there is substantial pleiotropic overlap in the developmental and immunological functions of genes involved in immune signaling and that pleiotropy would be associated with stronger signatures of evolutionary constraint. Our results suggest that pleiotropic immune genes do evolve more slowly than those having no known developmental functions and that signatures of constraint are particularly strong for pleiotropic immune genes that are broadly expressed across life stages. These results support the general yet untested hypothesis that pleiotropy can constrain immune system evolution, raising new fundamental questions about the benefits of maintaining pleiotropy in systems that need to rapidly adapt to changing pathogen pressures.