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Understanding the processes that link genotype to phenotype is a central challenge in biology. Despite progress in discovering genes associated with ecologically relevant traits, a poor understanding of the processes and functions via which molecules mediate evolutionary differences leaves us critically far from linking proximate and ultimate causes of evolution. This knowledge gap is particularly large in multifaceted phenotypes of ecological relevance such as life histories where multiple traits covary and influence fitness. In Atlantic salmon ( Salmo salar ), variation in a key life-history trait, maturation age, is largely linked to the transcription cofactor vestigial-like 3 ( vgll3 ). Here, we show that despite this simple genetic architecture, vgll3 genotype influences maturation age through a complex regulatory mechanism whereby it controls the expression of diverse pubertal signaling pathways. Using a multiomic approach in salmon testes, we show that the vgll3 genotype conferring early maturity up-regulates key genes controlling androgen production, cellular energy and adiposity, and TGF-β signaling, thereby increasing the likelihood of earlier pubertal initiation. By mapping VGLL3 regulatory elements we further show its interaction with distinct transcription factors in a genotype-dependent manner, thus coordinating differential activation of regulatory pathways. This study reveals the proximate mechanisms through which a genetically simple association leads to functionally complex molecular differences in a spectrum of cellular traits, thus explaining the molecular basis of pleiotropy in a large-effect gene. Our results indicate that evolution in correlated phenotypes, as exemplified by alternative life history strategies, can be dictated by the function of major life-history genes., Competing Interests: Competing interests statement:The authors declare no competing interest.

Recurrent genomic rearrangements at 16p11.2 BP4-5 represent one of the most common causes of genomic disorders. Originally associated with increased risk for autism spectrum disorder, schizophrenia, and intellectual disability, as well as adiposity and head circumference, these CNVs have since been associated with a plethora of phenotypic alterations, albeit with high variability in expressivity and incomplete penetrance. Here, we comprehensively review the pleiotropy associated with 16p11.2 BP4-5 rearrangements to shine light on its full phenotypic spectrum. Illustrating this phenotypic heterogeneity, we expose many parallels between findings gathered from clinical versus population-based cohorts, which often point to the same physiological systems, and emphasize the role of the CNV beyond neuropsychiatric and anthropometric traits. Revealing the complex and variable clinical manifestations of this CNV is crucial for accurate diagnosis and personalized treatment strategies for carrier individuals. Furthermore, we discuss areas of research that will be key to identifying factors contributing to phenotypic heterogeneity and gaining mechanistic insights into the molecular pathways underlying observed associations, while demonstrating how diversity in affected individuals, cohorts, experimental models, and analytical approaches can catalyze discoveries., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region's copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV's impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5's pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV's impact on BMI and EA, acting through trait-specific dosage mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cis-regulatory elements govern the specific patterns and dynamics of gene expression in cells during development, which are the fundamental mechanisms behind cell differentiation. However, the genomic characteristics of single-cell cis-regulatory elements closely linked to cell differentiation during development remain unclear. To explore this, we systematically analyzed ∼250,000 putative single-cell cis-regulatory elements obtained from snATAC-seq analysis of the developing mouse cerebellum. We found that over 80% of these single-cell cis-regulatory elements show pleiotropic effects, being active in 2 or more cell types. The pleiotropic degrees of proximal and distal single-cell cis-regulatory elements are positively correlated with the density and diversity of transcription factor binding motifs and GC content. There is a negative correlation between the pleiotropic degrees of single-cell cis-regulatory elements and their distances to the nearest transcription start sites, and proximal single-cell cis-regulatory elements display higher relevance strengths than distal ones. Furthermore, both proximal and distal single-cell cis-regulatory elements related to cell differentiation exhibit enhanced sequence-level evolutionary conservation, increased density and diversity of transcription factor binding motifs, elevated GC content, and greater distances from their nearest genes. Together, our findings reveal the general genomic characteristics of putative single-cell cis-regulatory elements and provide insights into the genomic and evolutionary mechanisms by which single-cell cis-regulatory elements regulate cell differentiation during development., Competing Interests: Conflict of Interest The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

AbstractHormones mediate sexual dimorphism by regulating sex-specific patterns of gene expression, but it is unclear how much of this regulation involves sex-specific hormone levels versus sex-specific transcriptomic responses to the same hormonal signal. Moreover, transcriptomic responses to hormones can evolve, but the extent to which hormonal pleiotropy in gene regulation is conserved across closely related species is not well understood. We addressed these issues by elevating testosterone levels in juvenile females and males of three Sceloporus lizard species before sexual divergence in circulating testosterone and then characterizing transcriptomic responses in the liver. In each species, more genes were responsive to testosterone in males than in females, suggesting that early developmental processes prime sex-specific transcriptomic responses to testosterone later in life. However, overall transcriptomic responses to testosterone were concordant between sexes, with no genes exhibiting sex-by-treatment interactions. By contrast, hundreds of genes exhibited species-by-treatment interactions, particularly when comparing distantly related species with different patterns of sexual dimorphism, suggesting evolutionary lability in gene regulation by testosterone. Collectively, our results indicate that early organizational effects may lead to sex-specific differences in the magnitude, but not the direction, of transcriptomic responses to testosterone and that the hormone-genome interface accrues regulatory changes over evolutionary time.

Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 18 variants, increasing the number of known SIgAD-associated variants to 27 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD., Competing Interests: Declaration of competing Interest C.W. receives funding from GSK and MSD and is a part time employee of GSK. These companies had no input into this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Adaptive evolution often involves structural variation affecting genes or cis-regulatory changes that engender novel and favorable gain-of-function gene regulation. Such mutation could result in a favorable dominant trait. At the same time, the gene product could be dosage sensitive if its change in concentration disrupts another trait. As a result, the mutant allele would display dosage-sensitive pleiotropy (DSP). By minimizing imbalance while conserving the favorable dominant effect, heterozygosity can increase fitness and result in heterosis. The properties of these alleles are consistent with evidence from multiple studies that indicate increased fitness of heterozygous regulatory mutations. DSP can help explain mysterious properties of heterosis as well as other effects of hybridization., Competing Interests: Declaration of interests The author acknowledges no competing interests., (Copyright © 2024 The Author. Published by Elsevier Ltd.. All rights reserved.)

Common wall lizards (Podarcis muralis) in Italy show a striking variation in body coloration across the landscape, with highly exaggerated black and green colors in hot and dry climates and brown and white colors in cool and wet climates. Males are more intensely colored than females, and previous work has suggested that the maintenance of variation in coloration across the landscape reflects climatic effects on the strength of male-male competition, and through this sexual selection. However climatic effects on the intensity of male-male competition would need to be exceptionally strong to fully explain the geographic patterns of color variation. Thus, additional processes may contribute to the maintenance of color variation. Here we test the hypothesis that selection for green and black ornamentation in the context of male-male competition is opposed by selection against ornamentation because the genes involved in the regulation of coloration have pleiotropic effects on thermal physiology, such that ornamentation is selected against in cool climates. Field observations revealed no association between body coloration and microhabitat use or field active body temperatures. Consistent with these field data, lizards at the extreme ends of the phenotypic distribution for body coloration did not show any differences in critical minimum temperature, preferred body temperature, temperature-dependent metabolic rate, or evaporative water loss when tested in the laboratory. Combined, these results provide no evidence that genes that underlie sexual ornamentation are selected against in cool climate because of pleiotropic effects on thermal biology., (© 2024 The Author(s). Journal of Experimental Zoology Part A: Ecological and Integrative Physiology published by Wiley Periodicals LLC.)

Background: To describe different clinical presentations of a same NR2E3 recessive mutation in two families and within one family., Design: Interventional family study., Results: Our first case was a one-year-old male child with high hyperopia and refractive accommodative esotropia. In retinal examination, peri-papillary sub-retinal fibrosis with a helicoid configuration was observed in both eyes. The parents and the only sibling had no pathologic findings in the eyes. The child showed to have severely reduced responses in both photopic and scotopic electroretinogram components. In the genetic investigation, a homozygous autosomal recessive mutation in the NR2E3 gene (IVS1-2A > C) was discovered in the affected child, while the other family members were heterozygous for this mutation. We followed up with the patient for 3 years and no new lesion developed during this period. The second case was a 13-year-old male child referred to the retina clinic for decreased vision in the right eye. In retina examination, there were nummular pigmentary changes at the level of retinal pigment epithelium and along the vascular arcades with foveo-schitic changes in both eyes. A choroidal neovascularization (CNV) was noticed in the macula of his right eye. The genetic evaluation proved the same mutation in the NR2E3 gene as in the first case. Family history was remarkable for an uncle, an aunt, and two cousins with night blindness., Conclusion: Same NR2E3 gene mutation can cause heterogeneous clinical manifestations such as slight retinal changes in the absence of any visual symptoms to high hyperopia associated with helicoid peri-papillary sub-retinal fibrosis., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

While schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) genetically correlate, the pleiotropy underlying response/resistance to drugs used in these disorders has not been investigated. The aim of this study is to analyze the genetic relationship between treatment-resistant schizophrenia (TRS), response to lithium in BD (respLi) and response to antidepressants in MDD (respAD) using the conditional/conjunctional false discovery rate (cond/conjFDR) methodology, based on the hypothesis that shared mechanisms related to a common psychopathology factor underlie these phenotypes. A cross-trait polygenic enrichment for TRS conditioned on associations with respLi was observed. The conjFDR analysis identified rs11631065 (chr15:66654304) as a shared locus between them. One of the genes at this locus is MAP2K1, previously reported as associated with TRS after conditioning on body mass index genome-wide association study (GWAS). The set of genes at TRS-respLi conjFDR < 0.95 showed enrichment in response to psychotropic drugs in severe mental disorders from GWAS Catalog as well as in neurodevelopment and synaptic pathways. In conclusion, our study constitutes the first evidence of a transdiagnostic genetic signal associated with response to different pharmacological treatments in psychotic and affective disorders. It is necessary to confirm these results when larger GWAS of these phenotypes are available., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Adolescent idiopathic scoliosis (AIS) and schizophrenia (SCZ) are two distinct conditions with poorly understood aetiologies that both emerge in otherwise healthy young adolescents. One rare genetic condition associated with both phenotypic outcomes is the 22q11.2 deletion (22q11DS). This microdeletion, encompassing 47 genes, occurs in approximately 1 in 2,148 live births and confers a 20-fold higher risk for both AIS and schizophrenia compared to the general population. In the general population (non-22q11DS carriers), AIS and SCZ have also been reported to be related and genetic studies suggest the involvement of genetic variants implicated in the central nervous functioning. In this study, our objective was to further investigate genetic overlaps between these conditions in the general population. Specifically, we aimed to explore the role of genes within the 22q11.2 region, not only in terms of common variants but also their potential impact on gene networks and biopathways., Methods: We used summary statistics from three genome-wide association studies (GWAS): two focused on AIS (n = 11,210), and one on schizophrenia (n = 36,989). To explore potential overlaps between the two conditions, we conducted a comparative analysis on the significance-based ranked single nucleotide polymorphisms (SNPs) that are associated with both AIS and SCZ. Next, we employed in silico analyses to assess gene-networks enrichment for the most significant SNPs and investigate the contribution of genes within the 22q11.2 region. Post-hoc analysis was conducted to explore the biological pathways correlated with SNPs significantly associated with both AIS and SCZ., Results: The in silico analyses revealed a significant (adjusted-p < 0.05) genetic overlap between SCZ and both AIS cohorts. The top 3% of the most significant SNPs associated with both conditions exhibited a distinct enrichment cluster which is unlikely to be a result of chance (p < 3e-04). The gene-networks analyses showed a significant overlap of 26-41% with the ones involving genes in the 22q11DS region. However, there was no overlap between SNPs in this region and the most significant SNPs identified in the GWAS., Conclusion: This study revealed compelling evidence that beyond the shared association with 22q11DS as a rare genetic variant, AIS and SCZ exhibit common genetic risk variants and an overlap of important genes. The gene networks enriched by the most significant SNPs for both conditions also intersect with the ones involving genes in the 22q11DS region. However, SNPs within this region were not overrepresented among the most significant SNPs from GWAS for both conditions. Notably, gene networks linked to the risk for both conditions suggest an involvement of biopathways related to cellular signaling and neuronal development., (© 2024. The Author(s).)

The vacuolar H + -ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic dominantly acting variants in ATP6V1B2, the gene encoding the V1B2 subunit, as underlying a clinically variable phenotypic spectrum including dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome. Here, we report on an individual with features fitting DOORS syndrome caused by dysregulated ATP6V1C1 function, expand the clinical features associated with ATP6V1B2 pathogenic variants, and provide evidence that these ATP6V1C1/ATP6V1B2 amino acid substitutions result in a gain-of-function mechanism upregulating V-ATPase function that drives increased lysosomal acidification. We demonstrate a disruptive effect of these ATP6V1B2/ATP6V1C1 variants on lysosomal morphology, localization, and function, resulting in a defective autophagic flux and accumulation of lysosomal substrates. We also show that the upregulated V-ATPase function affects cilium biogenesis, further documenting pleiotropy. This work identifies ATP6V1C1 as a new gene associated with a neurodevelopmental phenotype resembling DOORS syndrome, documents the occurrence of a phenotypic continuum between ZLS, and DDOD and DOORS syndromes, and classify these conditions as lysosomal disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dogs exhibit remarkable phenotypic diversity, particularly in behavioral traits, making them an excellent model for studying the genetic basis of complex behaviors. Behavioral traits such as aggression and fear are highly heritable among different dog breeds, but their genetic basis is largely unknown. We used the genome-wide association study (GWAS) to identify candidate genes associated with nine behavioral traits including; stranger-directed aggression (SDA), owner-directed aggression (ODA), dog-directed aggression (DDA), stranger-directed fear (SDF), nonsocial fear (NF), dog-directed fear (DDF), touch sensitivity (TS), separation-related behavior (SRB) and attachment attention-seeking (AAS). The observed behavioral traits were collected from 38,714 to 40,460 individuals across 108 modern dog breeds. We performed a GWAS based on a latent trait extracted using the confirmatory factor analysis (CFA) method with nine observable behavioral traits and compared the results with those from the GWAS of the observed traits. Using both observed-trait and latent-trait GWAS, we identified 41 significant SNPs that were common between both GWAS methods, of which 26 were pleiotropic, as well as 10 SNPs unique to the latent-trait GWAS, and 5 SNPs unique to the observed-trait GWAS discovered. These SNPs were associated with 21 genes in latent-trait GWAS and 22 genes in the observed-trait GWAS, with 19 genes shared by both. According to previous studies, some of the genes from this study have been reported to be related to behavioral and neurological functions in dogs. In the human population, these identified genes play a role in either the formation of the nervous system or are linked to various mental health conditions. Taken together, our findings suggest that latent-trait GWAS for behavioral traits in dogs identifies significant latent genes that are neurologically prioritized., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Throughout domestication, crop plants have gone through strong genetic bottlenecks, dramatically reducing the genetic diversity in today's available germplasm. This has also reduced the diversity in traits necessary for breeders to develop improved varieties. Many strategies have been developed to improve both genetic and trait diversity in crops, from backcrossing with wild relatives, to chemical/radiation mutagenesis, to genetic engineering. However, even with recent advances in genetic engineering we still face the rate limiting step of identifying which genes and mutations we should target to generate diversity in specific traits., Methods: Here, we apply a comparative evolutionary approach, pairing phylogenetic and expression analyses to identify potential candidate genes for diversifying soybean (Glycine max) canopy cover development via the nuclear auxin signaling gene families, while minimizing pleiotropic effects in other tissues. In soybean, rapid canopy cover development is correlated with yield and also suppresses weeds in organic cultivation., Results and Discussion: We identified genes most specifically expressed during early canopy development from the TIR1/AFB auxin receptor, Aux/IAA auxin co-receptor, and ARF auxin response factor gene families in soybean, using principal component analysis. We defined Arabidopsis thaliana and model legume species orthologs for each soybean gene in these families allowing us to speculate potential soybean phenotypes based on well-characterized mutants in these model species. In future work, we aim to connect genetic and functional diversity in these candidate genes with phenotypic diversity in planta allowing for improvements in soybean rapid canopy cover, yield, and weed suppression. Further development of this and similar algorithms for defining and quantifying tissue- and phenotype-specificity in gene expression may allow expansion of diversity in valuable phenotypes in important crops., Competing Interests: DF and RW have filed an invention disclosure related to the algorithm developed in this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ferreira Neres, Taylor, Bryant, Bargmann and Wright.)

Hearing difficulty (HD) is a major health burden in older adults. While ageing-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analysed a large-scale HD genome-wide association study (GWAS; ntotal = 501 825, 56% females) and GWAS data related to 3935 brain imaging-derived phenotypes (IDPs) assessed in up to 33 224 individuals (52% females) using multiple MRI modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait co-localization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 in males and 171 in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven of them, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a co-localization signal for the rs13026575 variant between HD, primary visual cortex volume and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4 + CD25 - IL17 + Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN., (© 2024. Higher Education Press.)

In animals, the nervous system evolved as the primary interface between multicellular organisms and the environment. As organisms became larger and more complex, the primary functions of the nervous system expanded to include the modulation and coordination of individual responsive cells via paracrine and synaptic functions as well as to monitor and maintain the organism's own internal environment. This was initially accomplished via paracrine signaling and eventually through the assembly of multicell circuits in some lineages. Cells with similar functions and centralized nervous systems have independently arisen in several lineages. We highlight the molecular mechanisms that underlie parallel diversifications of the nervous system.

Increasing crop yield depends on selecting and utilizing pleiotropic genes/alleles to improve multiple yield-related traits (YRTs) during crop breeding. However, synergistic improvement of YRTs is challenging due to the trade-offs between YRTs in breeding practices. Here, the favourable haplotypes of the TaCYP78A family are identified by analysing allelic variations in 1571 wheat accessions worldwide, demonstrating the selection and utilization of pleiotropic genes to improve yield and related traits during wheat breeding. The TaCYP78A family members, including TaCYP78A3, TaCYP78A5, TaCYP78A16, and TaCYP78A17, are organ size regulators expressed in multiple organs, and their allelic variations associated with various YRTs. However, due to the trade-offs between YRTs, knockdown or overexpression of TaCYP78A family members does not directly increase yield. Favourable haplotypes of the TaCYP78A family, namely A3/5/16/17Ap-Hap II, optimize the expression levels of TaCYP78A3/5/16/17-A across different wheat organs to overcome trade-offs and improve multiple YRTs. Different favourable haplotypes have both complementary and specific functions in improving YRTs, and their aggregation in cultivars under strong artificial selection greatly increase yield, even under various planting environments and densities. These findings provide new support and valuable genetic resources for molecular breeding of wheat and other crops in the era of Breeding 4.0., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Schizophrenia is a severe psychiatric disorder, associated with a reduction in life expectancy of 15-20 years. Available treatments are at least partially effective in most affected individuals, and personal resources such as resilience (successful adaptation despite adversity) and coping abilities (strategies used to deal with stressful or threatening situations), are important determinants of disease outcomes and long-term sustained recovery. Published findings support the existence of a genetic background underlying resilience and coping, with variable heritability estimates. However, genome-wide analyses concerning the genetic determinants of these personal resources, especially in the context of schizophrenia, are lacking. Here, we performed a genome-wide association study coupled with accessory analyses to investigate potential genetic determinants of resilience, coping and self-esteem in 490 schizophrenia patients. Results revealed a complex genetic background partly overlapping with that of neuroticism, worry and schizophrenia itself and support the importance of social aspects in shapingthese psychological constructs. Hippocampal neurogenesis and lipid metabolism appear to be potentially relevant biological underpinnings, and specific miRNAs such as miR-124 and miR-137 may warrant further studies as potential biomarkers. In conclusion, this study represents an important first step in the identification of genetic and biological correlates shaping resilience, coping resources and self-esteem in schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The aim of this study was to scan phenotypes in adulthood associated with polygenic risk scores (PRS) for childhood cancers with well-articulated genetic architectures-acute lymphoblastic leukemia (ALL), Ewing sarcoma, and neuroblastoma-to examine genetic pleiotropy. Furthermore, we aimed to determine which SNPs could drive associations. Per-SNP summary statistics were extracted for PRS calculation. Participants with white British ancestry were exclusively included for analyses. SNPs were queried from the UK Biobank genotype imputation data. Records from the cancer registry, death registry, and inpatient diagnoses were abstracted for phenome-wide scans. Firth logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) alongside corresponding p values, adjusting for age at recruitment and sex. A total of 244,332 unrelated white British participants were included. We observed a significant association between ALL-PRS and ALL (OR: 1.20e+24, 95% CI: 9.08e+14-1.60e+33). In addition, we observed a significant association between high-risk neuroblastoma PRS and nonrheumatic aortic valve disorders (OR: 43.9, 95% CI: 7.42-260). There were no significant phenotype associations with Ewing sarcoma and neuroblastoma PRS. Regarding individual SNPs, rs17607816 increased the risk of ALL (OR: 6.40, 95% CI: 3.26-12.57). For high-risk neuroblastoma, rs80059929 elevated the risk of atrioventricular block (OR: 3.04, 95% CI: 1.85-4.99). Our findings suggest that individuals with genetic susceptibility to ALL may face a lifelong risk for developing ALL, along with a genetic pleiotropic association between high-risk neuroblastoma and circulatory diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

High rates of metabolic risk factors contribute to premature mortality in patients with severe mental disorders, but the molecular underpinnings of this association are largely unknown. We performed the first analysis on shared genetic factors between severe mental disorders and metabolic traits considering the effect of sex. We applied an integrated analytical pipeline on the largest sex-stratified genome-wide association datasets available for bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and for body mass index (BMI) and waist-to-hip ratio (WHR) (all including participants of European origin). We observed extensive genetic overlap between all severe mental disorders and variants associated with BMI in women or men and identified several genetic loci shared between BD, or SZ and BMI in women (24 and 91, respectively) or men (13 and 208, respectively), with mixed directions of effect. A large part of the identified genetic variants showed sex differences in terms of location, genes modulated in adipose tissue and/or brain regions, and druggable targets. By providing a complete picture of disorder specific and cross-disorder shared genetic determinants, our results highlight potential sex differences in the genetic liability to metabolic comorbidities in patients with severe mental disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Observations of genetically repeated evolution (repeatability) in complex organisms are incongruent with the Fisher-Orr model, which implies that repeated use of the same gene should be rare when mutations are pleiotropic (i.e. affect multiple traits). When spatially divergent selection occurs in the presence of migration, mutations of large effect are more strongly favored, and hence, repeatability is more likely, but it is unclear whether this observation is limited by pleiotropy. Here, we explore this question using individual-based simulations of a two-patch model incorporating multiple quantitative traits governed by mutations with pleiotropic effects. We explore the relationship between fitness trade-offs and repeatability by varying the alignment between mutation effect and spatial variation in trait optima. While repeatability decreases with increasing trait dimensionality, trade-offs in mutation effects on traits do not strongly limit the contribution of a locus of large effect to repeated adaptation, particularly under increased migration. These results suggest that repeatability will be more pronounced for local rather than global adaptation. Whereas pleiotropy limits repeatability in a single-population model, when there is local adaptation with gene flow, repeatability can occur if some loci are able to produce alleles of large effect, even when there are pleiotropic trade-offs., Competing Interests: Conflicts of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

New genes (or young genes) are genetic novelties pivotal in mammalian evolution. However, their phenotypic impacts and evolutionary patterns over time remain elusive in humans due to the technical and ethical complexities of functional studies. Integrating gene age dating with Mendelian disease phenotyping, our research shows a gradual rise in disease gene proportion as gene age increases. Logistic regression modeling indicates that this increase in older genes may be related to their longer sequence lengths and higher burdens of deleterious de novo germline variants (DNVs). We also find a steady integration of new genes with biomedical phenotypes into the human genome over macroevolutionary timescales (~0.07% per million years). Despite this stable pace, we observe distinct patterns in phenotypic enrichment, pleiotropy, and selective pressures across gene ages. Notably, young genes show significant enrichment in diseases related to the male reproductive system, indicating strong sexual selection. Young genes also exhibit disease-related functions in tissues and systems potentially linked to human phenotypic innovations, such as increased brain size, musculoskeletal phenotypes, and color vision. We further reveal a logistic growth pattern of pleiotropy over evolutionary time, indicating a diminishing marginal growth of new functions for older genes due to intensifying selective constraints over time. We propose a "pleiotropy-barrier" model that delineates higher potentials for phenotypic innovation in young genes compared to older genes, a process that is subject to natural selection. Our study demonstrates that evolutionarily new genes are critical in influencing human reproductive evolution and adaptive phenotypic innovations driven by sexual and natural selection, with low pleiotropy as a selective advantage., Competing Interests: Competing Interests: The authors have declared that no competing interests exist.

Advancing male age is often hypothesized to reduce both male fertility and offspring quality due to reproductive senescence. However, the effects of advancing male age on reproductive output and offspring quality are not always deleterious. For example, older fathers might buffer the effects of reproductive senescence by terminally investing in reproduction. Similarly, males that survive to reproduce at an old age might carry alleles that confer high viability (viability selection), which are then inherited by offspring, or might have high reproductive potential (selective disappearance). Differentiating these mechanisms requires an integrated experimental study of paternal survival and reproductive performance, as well as offspring quality, which is currently lacking. Using a cross-sectional study in Drosophila melanogaster, we test the effects of paternal age at conception (PAC) on paternal survival and reproductive success, and on the lifespans of sons. We discover that mating at an old age is linked with decreased future male survival, suggesting that mating-induced mortality is possibly due to old fathers being frail. We find no evidence for terminal investment and show that reproductive senescence in fathers does not onset until their late-adult life. Additionally, we find that as a father's lifespan increases, his probability of siring offspring increases for older PAC treatments only. Lastly, we show that sons born to older fathers live longer than those born to younger fathers due to viability selection. Collectively, our results suggest that advancing paternal age is not necessarily associated with deleterious effects for offspring and may even lead to older fathers producing longer-lived offspring., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE).)

This study offers insights into the genetic and biological connections between nine common metabolic diseases using data from genome-wide association studies. Our goal is to unravel the genetic interactions and biological pathways of these complex diseases, enhancing our understanding of their genetic architecture. We employed a range of advanced analytical techniques to explore the genetic correlations and shared genetic variants of these diseases. These methods include Linked Disequilibrium Score Regression, High-Definition Likelihood (HDL), genetic analysis combining multiplicity and annotation (GPA), two-sample Mendelian randomization analyses, analysis under the multiplicity-complex null hypothesis (PLACO), and Functional mapping and annotation of genetic associations (FUMA). Additionally, Bayesian co-localization analyses were used to examine associations of specific loci across traits. Our study discovered significant genomic correlations and shared loci, indicating complex genetic interactions among these metabolic diseases. We found several shared single nucleotide variants and risk loci, notably highlighting the role of the immune system and endocrine pathways in these diseases. Particularly, rs2476601 and its associated gene PTPN22 appear to play a crucial role in the connection between type 2 diabetes mellitus, hypothyroidism/mucous oedema and hypoglycaemia. These findings enhance our understanding of the genetic underpinnings of these diseases and open new potential avenues for targeted therapeutic and preventive strategies. The results underscore the importance of considering pleiotropic effects in deciphering the genetic architecture of complex diseases, especially metabolic ones., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: Previous studies have shown that inflammatory bowel disease (IBD) is associated with osteoporosis (OP) and bone mineral density (BMD), but the underlying genetic mechanisms are unclear. Our study wanted to explore the genetic and causal relationship between IBD and OP., Materials and Methods: Based on large-scale genome-wide association summary statistics and individual-level datasets (i.e., the UK Biobank), this study performed linkage disequilibrium score regression (LDSC), pleiotropic analysis under the composite null hypothesis (PLACO), and Mendelian randomization (MR) analyses to explore the genetic association, the pleiotropic genes and the causal relationship between IBD and BMD., Results: LDSC revealed significant genetic correlations between IBD and BMD (e.g., forearm BMD (rg = -0.3479, P = 0.019) and femoral neck BMD (rg = -0.1335, P = 0.0307). PLACO identified 14 overlapping pleiotropic loci, 1 shared risk gene (CDYL), and multiple shared pathways, revealing possible mechanisms for IBD and OP. MR analysis demonstrated a causal association between IBD and BMD., Conclusions: Our study indicates that IBD may increase the risk of OP and reveals a complex genetic mechanism linking IBD and the risk of osteoporosis, which has important implications for diagnosing and treating IBD and OP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%-80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E-08] and rs2221169 [p = 4.5E-08]) and one locus with marginal significance (rs187523265 [p = 5.22E-08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration., (© 2024 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)

Carotenoids play essential roles in photosynthesis, photoprotection, and human health. Efforts to increase carotenoid content in several staple crops have been successful through both conventional selection and genetic engineering methods. Interestingly, in some cases, altering carotenoid content has had unexpected effects on other aspects of plant metabolism, impacting traits like sugar content, dry matter percentage, fatty acid content, stress tolerance, and phytohormone concentrations. Studies across several diverse crop species have identified negative correlations between carotenoid and starch contents, as well as positive correlations between carotenoids and soluble sugars. Collectively, these reports suggest a metabolic interaction between carotenoids and carbohydrates. We synthesize evidence pointing to four hypothesized mechanisms: (1) direct competition for precursors; (2) physical interactions in plastids; (3) influences of sugar or apocarotenoid signaling networks; and (4) nonmechanistic population or statistical sources of correlations. Though the carotenoid biosynthesis pathway is well understood, the regulation and interactions of carotenoids, especially in nonphotosynthetic tissues, remain unclear. This topic represents an underexplored interplay between primary and secondary metabolism where further research is needed., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral-cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5' to 3' end of the gene (Pearson's r = 0.33, p = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype-phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APC gene variants in these behavioral and cognitive challenges., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Sarcopenia is a progressive age-related muscle disease characterized by low muscle strength, quantity and quality, and low physical performance. The clinical overlap between these subphenotypes (reduction in muscle strength, quantity and quality, and physical performance) was evidenced, but the genetic overlap is still poorly investigated. Herein, we investigated whether there is a genetic overlap amongst sarcopenia subphenotypes in the search for more effective molecular markers for this disease. For that, a Bioinformatics approach was used to identify and characterize pleiotropic effects at the genome, loci and gene levels using Genome-wide association study results. As a result, a high genetic correlation was identified between gait speed and muscle strength (rG=0.5358, p=3.39 × 10 -8 ). Using a Pleiotropy-informed conditional and conjunctional false discovery rate method we identified two pleiotropic loci for muscle strength and gait speed, one of them was nearby the gene PHACTR1. Moreover, 11 pleiotropic loci and 25 genes were identified for muscle mass and muscle strength. Lastly, using a gene-based GWAS approach three candidate genes were identified in the overlap of the three Sarcopenia subphenotypes: FTO, RPS10 and CALCR. The current study provides evidence of genetic overlap and pleiotropy among sarcopenia subphenotypes and highlights novel candidate genes and molecular markers associated with the risk of sarcopenia., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

The highly polygenic nature of human longevity renders pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between aging-related traits (ARTs), we aimed to model the additive variance in lifespan as a function of the cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores (iLGSs) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts (the Scripps Wellderly cohort and the Medical Genome Reference Bank (MRGB)) and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates of iLGS, we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at a higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated with iLGS highlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan., (© 2024. The Author(s).)

Background and Hypothesis: Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated., Study Design: Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci., Study Results: We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy., Conclusions: This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial., Objective: We aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers., Methods: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped., Results: The study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link., Conclusion: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Joint association analysis of multiple traits with multiple genetic variants can provide insight into genetic architecture and pleiotropy, improve trait prediction, and increase power for detecting association. Furthermore, some traits are naturally high-dimensional, e.g., images, networks, or longitudinally measured traits. Assessing significance for multitrait genetic association can be challenging, especially when the sample has population sub-structure and/or related individuals. Failure to adequately adjust for sample structure can lead to power loss and inflated type 1 error, and commonly used methods for assessing significance can work poorly with a large number of traits or be computationally slow. We developed JASPER, a fast, powerful, robust method for assessing significance of multitrait association with a set of genetic variants, in samples that have population sub-structure, admixture, and/or relatedness. In simulations, JASPER has higher power, better type 1 error control, and faster computation than existing methods, with the power and speed advantage of JASPER increasing with the number of traits. JASPER is potentially applicable to a wide range of association testing applications, including for multiple disease traits, expression traits, image-derived traits, and microbiome abundances. It allows for covariates, ascertainment, and rare variants and is robust to phenotype model misspecification. We apply JASPER to analyze gene expression in the Framingham Heart Study, where, compared to alternative approaches, JASPER finds more significant associations, including several that indicate pleiotropic effects, most of which replicate previous results, while others have not previously been reported. Our results demonstrate the promise of JASPER for powerful multitrait analysis in structured samples., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data. To address these challenges, we propose a multi-context multivariable integrative MR framework, mintMR, for mapping expression and molecular traits as joint exposures. It models the effects of molecular exposures across multiple tissues in each gene region, while simultaneously estimating across multiple gene regions. It uses eQTLs with consistent effects across more than one tissue type as IVs, improving IV consistency. A major innovation of mintMR involves employing multi-view learning methods to collectively model latent indicators of disease relevance across multiple tissues, molecular traits, and gene regions. The multi-view learning captures the major patterns of disease relevance and uses these patterns to update the estimated tissue relevance probabilities. The proposed mintMR iterates between performing a multi-tissue MR for each gene region and joint learning the disease-relevant tissue probabilities across gene regions, improving the estimation of sparse effects across genes. We apply mintMR to evaluate the causal effects of gene expression and DNA methylation for 35 complex traits using multi-tissue QTLs as IVs. The proposed mintMR controls genome-wide inflation and offers insights into disease mechanisms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Genetic variants used as instruments for exposures in Mendelian randomisation (MR) analyses may have horizontal pleiotropic effects (i.e., influence outcomes via pathways other than through the exposure), which can undermine the validity of results. We examined the extent of this using smoking behaviours as an example. We first ran a phenome-wide association study in UK Biobank, using a smoking initiation genetic instrument. From the most strongly associated phenotypes, we selected those we considered could either plausibly or not plausibly be caused by smoking. We examined associations between genetic instruments for smoking initiation, smoking heaviness and lifetime smoking and these phenotypes in UK Biobank and the Avon Longitudinal Study of Parents and Children (ALSPAC). We conducted negative control analyses among never smokers, including children. We found evidence that smoking-related genetic instruments were associated with phenotypes not plausibly caused by smoking in UK Biobank and (to a lesser extent) ALSPAC. We observed associations with phenotypes among never smokers. Our results demonstrate that smoking-related genetic risk scores are associated with unexpected phenotypes that are less plausibly downstream of smoking. This may reflect horizontal pleiotropy in these genetic risk scores, and we would encourage researchers to exercise caution this when using these and genetic risk scores for other complex behavioural exposures. We outline approaches that could be taken to consider this and overcome issues caused by potential horizontal pleiotropy, for example, in genetically informed causal inference analyses (e.g., MR) it is important to consider negative control outcomes and triangulation approaches, to avoid arriving at incorrect conclusions., (© 2024 The Author(s). Genetic Epidemiology published by Wiley Periodicals LLC.)

Regulatory genetic variation shapes gene expression, providing an important mechanism connecting DNA variation and complex traits. The causal relationships between gene expression and complex traits remain poorly understood. Here, we integrated transcriptomes and 46 genetically complex growth traits in a large cross between two strains of the yeast Saccharomyces cerevisiae . We discovered thousands of genetic correlations between gene expression and growth, suggesting potential functional connections. Local regulatory variation was a minor source of these genetic correlations. Instead, genetic correlations tended to arise from multiple independent trans -acting regulatory loci. Trans -acting hotspots that affect the expression of numerous genes accounted for particularly large fractions of genetic growth variation and of genetic correlations between gene expression and growth. Genes with genetic correlations were enriched for similar biological processes across traits, but with heterogeneous direction of effect. Our results reveal how trans -acting regulatory hotspots shape complex traits by altering cellular states.

Background and Aims: Hepatic steatosis is known to be heritable, but its genetic basis is mostly uncharacterized. Steatosis is associated with metabolic and adiposity features; recent studies hypothesize that shared genetic effects between these traits could account for some of the unexplained heritability. This study aimed to quantify these genetic associations in a family-based sample of non-Hispanic white adults., Methods and Results: 704 participants (18-95 years, 55.8% female) from the Fels Longitudinal Study with an MRI assessment of liver fat were included. Quantitative genetic analyses estimated the age- and sex-adjusted heritability of individual traits and the genetic correlations within trait pairs. Mean liver fat was 5.95% (SE = 0.23) and steatosis (liver fat >5.56%) was present in 29.8% of participants. Heritability (h 2 ± SE) of steatosis was 0.72 ± 0.17 (p = 6.80e -6 ). All other traits including liver enzymes, fasting glucose, HOMA-IR, visceral and subcutaneous adipose tissue (VAT, SAT), body mass index, body fat percent, waist circumference, lipids and blood pressure were also heritable. Significant genetic correlations were found between liver fat and all traits except aspartate aminotransferase (AST), and among most trait pairs. Highest genetic correlations were between liver fat and HOMA-IR (0.85 ± 0.08, p = 1.73e -8 ), fasting glucose and ALT (0.89 ± 0.26, p = 6.68e -5 ), and HOMA-IR with: waist circumference (0.81 ± 0.12, p = 3.76e -6 ), body fat percent (0.78 ± 0.12 p = 2.42e -5 ) and VAT (0.73 ± 0.07, p = 6.37e -8 )., Conclusions: Common genes may exist between liver fat accumulation, metabolic features and adiposity phenotypes., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest concerning this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This study aims to explore the genetic architecture shared between Attention-Deficit/Hyperactivity Disorder (ADHD) and risk behavior., Methods: Based on the latest large-scale Genome-wide association studies (GWAS), we firstly employed Linkage disequilibrium score regression (LDSC) and Local Analysis of Variant Association (LAVA) to investigate the genetic correlation between risk behavior and ADHD. Then, we conducted cross-trait analysis to identified the Pleiotropic loci. Finally, bidirectional Mendelian randomization analysis (MR) was applied to examine the causal relationship., Results: We found a significant positive genetic correlation between ADHD and risk-taking behavior (rg = 0.351, p = 6.50E-37). The cross-trait meta-analysis identified 27 significant SNPs shared between ADHD and risk behavior. The most significant locus, located near the CADM2 gene on chromosome 3, had been identified associated with this two trait (pADHD = 3.07E-05 and prisk-taking behavior = 2.47E-30). The same situation can also be observed near the FOXP2 gene on chromosome 7 (rs8180817, pmeta = 5.72E-21). We found CCDC171 gene and other genes played a significant role in ADHD and risk behavior in mRNA level. Bidirectional MR analysis found a causal relationship between them., Limitation: The majority of our data sources were of European origin, which may limit the generalizability of our findings to other ethnic populations., Conclusion: This article reveals in depth the shared genetic structure between ADHD and risk-taking behavior, finding a significant positive genetic correlation between ADHD and risk-taking behavior. Providing insights for the future treatment and management of these two traits., Competing Interests: Declaration of competing interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Drought adaptation is critical to many tree species persisting under climate change, however our knowledge of the genetic basis for trees to adapt to drought is limited. This knowledge gap impedes our fundamental understanding of drought response and application to forest production and conservation. To improve our understanding of the genomic determinants, architecture, and trait constraints, we assembled a reference genome and detected ~ 6.5 M variants in 432 phenotyped individuals for the foundational tree Corymbia calophylla., Results: We found 273 genomic variants determining traits with moderate heritability (h 2 SNP  = 0.26-0.64). Significant variants were predominantly in gene regulatory elements distributed among several haplotype blocks across all chromosomes. Furthermore, traits were constrained by frequent epistatic and pleiotropic interactions., Conclusions: Our results on the genetic basis for drought traits in Corymbia calophylla have several implications for the ability to adapt to climate change: (1) drought related traits are controlled by complex genomic architectures with large haplotypes, epistatic, and pleiotropic interactions; (2) the most significant variants determining drought related traits occurred in regulatory regions; and (3) models incorporating epistatic interactions increase trait predictions. Our findings indicate that despite moderate heritability drought traits are likely constrained by complex genomic architecture potentially limiting trees response to climate change., (© 2024. The Author(s).)

Rice ( Oryza sativa ) is a cereal crop with a starchy endosperm. Starch is composed of amylose and amylopectin. Amylose content (AC) is the principal determinant of rice quality, but varieties with similar ACs can still vary substantially in their quality. In this study, we analyzed the total AC (TAC) and its constituent fractions, the hot water-soluble amylose content (SAC) and hot water-insoluble amylose content (IAC), in two sets of related chromosome segment substitution lines of rice with a common genetic background grown in two years. We searched for quantitative trait loci (QTLs) associated with SAC, IAC, and TAC and identified one common QTL ( qSAC-6 , qIAC-6 , and qTAC-6 ) on chromosome 6. Map-based cloning revealed that the gene underlying the trait associated with this common QTL is Waxy ( Wx ). An analysis of the colors of soluble and insoluble starch-iodine complexes and their λ max values (wavelengths at the positions of their peak absorbance values) as well as gel permeation chromatography revealed that Wx is responsible for the biosynthesis of amylose, comprising a large proportion of the soluble fractions of the SAC. Wx is also involved in the biosynthesis of long chains of amylopectin, comprising the hot water-insoluble fractions of the IAC. These findings highlight the pleiotropic effects of Wx on the SAC and IAC. This pleiotropy indicates that these traits have a positive genetic correlation. Therefore, further studies of rice quality should use rice varieties with the same Wx genotype to eliminate the pleiotropic effects of this gene, allowing the independent relationship between the SAC or IAC and rice quality to be elucidated through a multiple correlation analysis. These findings are applicable to other valuable cereal crops as well.

Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM., Competing Interests: Declaration of interests J.G. is named as an inventor on PCT patent application #15/878,640 entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018, and issued on January 26, 2021, as US Patent No. 10900082. J.G. is paid for editorial work for the journal Complex Psychiatry (Karger). D.E. is an ad hoc consultant for Alcon, Dutch Ophthalmic, GelMEDIX, and Genentech; reports research funding from Neurotech and Unity Biotechnology; is a member of the Advisory Board and Stockholder for InGel Therapeutics, Pykus Therapeutics, and RetMap; reports being Advisor, Patents, Royalties, and Stockholder in Aldeyra Therapeutics; and is a member of the Data Safety Monitoring Board for Asclepix. M.B.S. has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sumitomo Pharma, and Roche/Genentech. M.B.S. has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America., (Published by Elsevier Inc.)

Cowpeas ( Vigna unguiculata L. Walp) have been credible constituents of nutritious food and forage in human and animal diets since the Neolithic era. The modern technique of Diversity Array Technology (DArTseq) is both cost-effective and rapid in producing thousands of high-throughputs, genotyped, single nucleotide polymorphisms (SNPs) in wide-genomic analyses of genetic diversity. The aim of this study was to assess the heterogeneity in cowpea genotypes using DArTseq-derived SNPs. A total of 92 cowpea genotypes were selected, and their fourteen-day-old leaves were freeze-dried for five days. DNA was extracted using the CTAB protocol, genotyped using DArTseq, and analysed using DArTsoft14. A total of 33,920 DArTseq-derived SNPs were recalled for filtering analysis, with a final total of 16,960 SNPs. The analyses were computed using vcfR, poppr, and ape in R Studio v1.2.5001-3 software. The heatmap revealed that the TVU 9596 (SB26), Orelu (SB72), 90K-284-2 (SB55), RV 403 (SB17), and RV 498 (SB16) genotypes were heterogenous. The mean values for polymorphic information content, observed heterozygosity, expected heterozygosity, major allele frequency, and the inbreeding coefficient were 0.345, 0.386, 0.345, 0.729, and 0.113, respectively. Moreover, they validated the diversity of the evaluated cowpea genotypes, which could be used for potential breeding programmes and management of cowpea germplasm.

Angiotensin-convertingenzyme 2 (ACE2) has dual functions, regulating cardiovascular physiology and serving as the receptor for coronaviruses. Bats, the only true flying mammals and natural viral reservoirs, have evolved positive alterations in traits related to both functions of ACE2. This suggests significant evolutionary changes in ACE2 during bat evolution. To test this hypothesis, we examine the selection pressure in ACE2 along the ancestral branch of all bats (AncBat-ACE2), where powered flight and bat-coronavirus coevolution occurred, and detect a positive selection signature. To assess the functional effects of positive selection, we resurrect AncBat-ACE2 and its mutant (AncBat-ACE2-mut) created by replacing the positively selected sites. Compared to AncBat-ACE2-mut, AncBat-ACE2 exhibits stronger enzymatic activity, enhances mice's performance in exercise fatigue, and shows lower affinity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings indicate the functional pleiotropy of positive selection in the ancient ACE2 of bats, providing an alternative hypothesis for the evolutionary origin of bats' defense against coronaviruses., Competing Interests: Competing interests statement:The authors declare no competing interest.

We present shaPRS, a method that leverages widespread pleiotropy between traits or shared genetic effects across ancestries, to improve the accuracy of polygenic scores. The method uses genome-wide summary statistics from two diseases or ancestries to improve the genetic effect estimate and standard error at SNPs where there is homogeneity of effect between the two datasets. When there is significant evidence of heterogeneity, the genetic effect from the disease or population closest to the target population is maintained. We show via simulation and a series of real-world examples that shaPRS substantially enhances the accuracy of polygenic risk scores (PRSs) for complex diseases and greatly improves PRS performance across ancestries. shaPRS is a PRS pre-processing method that is agnostic to the actual PRS generation method, and as a result, it can be integrated into existing PRS generation pipelines and continue to be applied as more performant PRS methods are developed over time., Competing Interests: Declaration of interests C.A.A. has received consultancy or lectureship fees from Genomics plc, BridgeBio, Inc., and GSK. C.W. receives funding from GSK and MSD and is a part time employee of GSK. These companies had no input on this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Despite the recognition of attention deficit hyperactivity disorder (ADHD) as a multifaceted neurodevelopmental disorder, its core causes are still ambiguous. The objective of this study was to explore if the traits of circulating immune cells contribute causally to susceptibility to ADHD., Methods: By employing a unified GWAS summary data covering 731 immune traits from the GWAS Catalog (accession numbers from GCST0001391 to GCST0002121), our analysis focused on the flow cytometry of lymphocyte clusters, encompassing 3,757 Sardinians, to identify genetically expected immune cells. Furthermore, we obtained summarized GWAS statistics from the Psychiatric Genomics Consortium to evaluate the genetic forecasting of ADHD. The studies employed ADHD2019 (20,183 cases and 35,191 controls from the 2019 GWAS ADHD dataset) and ADHD2022 (38,691 cases and 275,986 controls from the 2022 GWAS ADHD dataset). Through the examination of genome-wide association signals, we identified shared genetic variances between circulating immune cells and ADHD, employing the comprehensive ADHD2022 dataset. We primarily utilized inverse variance weighted (IVW) and weighted median methods in our Mendelian randomization research and sensitivity assessments to evaluate diversity and pleiotropy., Results: After adjusting for false discovery rate (FDR), three distinct immunophenotypes were identified as associated with the risk of ADHD: CD33 in Im MDSC (OR=1.03, CI: 1.01~1.04, P =3.04×10 -5 , P FDR =0.015), CD8 br NKT %T cell (OR=1.08, 95%CI: 1.04~1.12, P =9.33×10 -5 , P FDR =0.023), and CD8 br NKT %lymphocyte (OR=1.08, 95%CI: 1.03~1.12, P =3.59×10 -4 , P FDR =0.066). Furthermore, ADHD showed no statistical effects on immunophenotypes. It's worth noting that 20 phenotypes exist where ADHD's appearance could diminish 85% of immune cells, including FSC-A in myeloid DC (β= -0.278, 95% CI: 0.616~0.931, P =0.008), CD3 in CD45RA- CD4+ (β= -0.233, 95% CI: 0.654~0.960, P =0.017), CD62L- monocyte AC (β=0.227, 95% CI: 0.038~1.518, P =0.019), CD33 in CD33 br HLA DR+ CD14dim (β= -0.331, 95% CI: 0.543~0.950, P =0.020), and CD25 in CD39+ resting Treg (β=0.226, 95% CI: 1.522, P =0.022), and FSC-A in monocytes (β= -0.255, 95% CI: 0.621~0.967, P =0.234), among others., Conclusion: Studies indicate that the immune system's response influences the emergence of ADHD. The findings greatly improve our understanding of the interplay between immune responses and ADHD risk, aiding in the development of treatment strategies from an immunological perspective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jue, Dan-fei, Fang-fang, Ke-pin, Jia-ye, Hui-ting, Xiao-bo and Jian.)

Coronary artery disease (CAD) is a common comorbidity of type 2 diabetes mellitus (T2DM). However, the pathophysiology connecting these two phenotypes remains to be further understood. Combined analysis in multi-ethnic populations can help contribute to deepening our understanding of biological mechanisms caused by shared genetic loci. We applied genetic correlation analysis and then performed conditional and joint association analyses in Chinese, Japanese, and European populations to identify the genetic variants jointly associated with CAD and T2DM. Next, the associations between genes and the two traits were also explored. Finally, fine-mapping and functional enrichment analysis were employed to identify the potential causal variants and pathways. Genetic correlation results indicated significant genetic overlap between CAD and T2DM in the three populations. Over 10,000 shared signals were identified, and 587 were shared by East Asian and European populations. Fifty-six novel shared genes were found to have significant effects on both CAD and T2DM. Most loci were fine-mapped to plausible causal variant sets. Several similarities and differences of the involved genes in GO terms and KEGG pathways were revealed across East Asian and European populations. These findings highlight the importance of immunoregulation, neuroregulation, heart development, and the regulation of glucose metabolism in shared etiological mechanisms between CAD and T2DM.

This article presents the concept of Antagonistic Pathogenic Pleiotropy, in which an abnormality that causes a specific pathology can simultaneously reduce other morbidities through unrelated mechanisms, resulting in the pathology causing less morbidity or mortality than expected. The concept is illustrated by the case of essential thrombocythemia (ET). Patients with ET have substantially elevated platelets and are therefore expected to have increased thrombotic events leading to reduced life expectancy. However, patients with ET do not have reduced life expectancy. A possible explanation is that elevated platelets produce higher levels of platelet factor 4 (PF4), which has been found to reduce age-associated decline in immune and cognitive function in mice and has been suggested as a treatment for age-associated illness. The benefit of elevated PF4 is hypothesized to balance the increased morbidity from hematological causes. Searches for other indications where a well-defined pathology is not associated with concomitant reduction in overall mortality may be a route to identifying factors that could protect against, prevent, or treat chronic disease.

Mendelian randomization (MR) leverages genetic information to examine the causal relationship between phenotypes allowing for the presence of unmeasured confounders. MR has been widely applied to unresolved questions in epidemiology, making use of summary statistics from genome-wide association studies on an increasing number of human traits. However, an understanding of essential concepts is necessary for the appropriate application and interpretation of MR. This review aims to provide a non-technical overview of MR and demonstrate its relevance to psychiatric research. We begin with the origins of MR and the reasons for its recent expansion, followed by an overview of its statistical methodology. We then describe the limitations of MR, and how these are being addressed by recent methodological advances. We showcase the practical use of MR in psychiatry through three illustrative examples - the connection between cannabis use and psychosis, the link between intelligence and schizophrenia, and the search for modifiable risk factors for depression. The review concludes with a discussion of the prospects of MR, focusing on the integration of multi-omics data and its extension to delineating complex causal networks.