More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles.

Introduction: Many loci segregate alleles classified as "genetic diseases" due to their deleterious effects on health. However, some disease alleles have been reported to show beneficial effects under certain conditions or in certain populations. The beneficial effects of these antagonistically pleiotropic alleles may explain their continued prevalence, but the degree to which antagonistic pleiotropy is common or rare is unresolved. We surveyed the medical literature to identify examples of antagonistic pleiotropy to help determine whether antagonistic pleiotropy appears to be rare or common. Results: We identified ten examples of loci with polymorphisms for which the presence of antagonistic pleiotropy is well supported by detailed genetic or epidemiological information in humans. One additional locus was identified for which the supporting evidence comes from animal studies. These examples complement over 20 others reported in other reviews. Discussion: The existence of more than 30 identified antagonistically pleiotropic human disease alleles suggests that this phenomenon may be widespread. This poses important implications for both our understanding of human evolutionary genetics and our approaches to clinical treatment and disease prevention, especially therapies based on genetic modification.

Autistic traits in youth with familial adenomatous polyposis: A Dutch-Canadian case-control study.

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.

Pleiotropic effects on Sarcopenia subphenotypes point to potential molecular markers for the disease.

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.

Epistasis and pleiotropy-induced variation for plant breeding.

Epistasis refers to nonallelic interaction between genes that cause bias in estimates of genetic parameters for a phenotype with interactions of two or more genes affecting the same trait. Partitioning of epistatic effects allows true estimation of the genetic parameters affecting phenotypes. Multigenic variation plays a central role in the evolution of complex characteristics, among which pleiotropy, where a single gene affects several phenotypic characters, has a large influence. While pleiotropic interactions provide functional specificity, they increase the challenge of gene discovery and functional analysis. Overcoming pleiotropy-based phenotypic trade-offs offers potential for assisting breeding for complex traits. Modelling higher order nonallelic epistatic interaction, pleiotropy and non-pleiotropy-induced variation, and genotype × environment interaction in genomic selection may provide new paths to increase the productivity and stress tolerance for next generation of crop cultivars. Advances in statistical models, software and algorithm developments, and genomic research have facilitated dissecting the nature and extent of pleiotropy and epistasis. We overview emerging approaches to exploit positive (and avoid negative) epistatic and pleiotropic interactions in a plant breeding context, including developing avenues of artificial intelligence, novel exploitation of large-scale genomics and phenomics data, and involvement of genes with minor effects to analyse epistatic interactions and pleiotropic quantitative trait loci, including missing heritability.

Evaluating the link between immune characteristics and attention deficit hyperactivity disorder through a bi-directional Mendelian randomization study.

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, PFDR =0.015), CD8br NKT %T cell (OR=1.08, 95%CI: 1.04~1.12, P=9.33×10-5, PFDR =0.023), and CD8br NKT %lymphocyte (OR=1.08, 95%CI: 1.03~1.12, P=3.59×10-4, PFDR =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 (ß= -0.278, 95% CI: 0.616~0.931, P=0.008), CD3 in CD45RA- CD4+ (ß= -0.233, 95% CI: 0.654~0.960, P=0.017), CD62L- monocyte AC (ß=0.227, 95% CI: 0.038~1.518, P=0.019), CD33 in CD33br HLA DR+ CD14dim (ß= -0.331, 95% CI: 0.543~0.950, P=0.020), and CD25 in CD39+ resting Treg (ß=0.226, 95% CI: 1.522, P=0.022), and FSC-A in monocytes (ß= -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.

Glycoprotein Acetyls Is a Novel Biomarker Predicting Cardiovascular Complications in Rheumatoid Arthritis.

The relationship between rheumatoid arthritis (RA) and early onset atherosclerosis is well depicted, each with an important inflammatory component. Glycoprotein acetyls (GlycA), a novel biomarker of inflammation, may play a role in the manifestation of these two inflammatory conditions. The present study examined a potential mediating role of GlycA within the RA-atherosclerosis relationship to determine whether it accounts for the excess risk of cardiovascular disease over that posed by lipid risk factors. The UK Biobank dataset was acquired to establish associations among RA, atherosclerosis, GlycA, and major lipid factors: total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TGs). Genome-wide association study summary statistics were collected from various resources to perform genetic analyses. Causality among variables was tested using Mendelian Randomization (MR) analysis. Genes of interest were identified using colocalization analysis and gene enrichment analysis. MR results appeared to indicate that the genetic relationship between GlycA and RA and also between RA and atherosclerosis was explained by horizontal pleiotropy (p-value = 0.001 and <0.001, respectively), while GlycA may causally predict atherosclerosis (p-value = 0.017). Colocalization analysis revealed several functionally relevant genes shared between GlycA and all the variables assessed. Two loci were apparent in all relationships tested and included the HLA region as well as SLC22A1. GlycA appears to mediate the RA-atherosclerosis relationship through several possible pathways. GlycA, although pleiotropically related to RA, appears to causally predict atherosclerosis. Thus, GlycA is suggested as a significant factor in the etiology of atherosclerosis development in RA.

Pleiotropy of positive selection in ancient ACE2 suggests an alternative hypothesis for bat-specific adaptations to host coronaviruses.

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.

Shared Genetic Architectures between Coronary Artery Disease and Type 2 Diabetes Mellitus in East Asian and European Populations.

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.

Genetic Heterogeneity in Cowpea Genotypes (Vigna unguiculata L. Walp) Using DArTseq (GBS)-Derived Single Nucleotide Polymorphisms.

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.

Genomic determinants, architecture, and constraints in drought-related traits in Corymbia calophylla.

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 (h2SNP = 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.

Most genetic roots of fungal and animal aging are hundreds of millions of years old according to phylostratigraphy analyses of aging networks.

Few studies have systematically analyzed how old aging is. Gaining a more accurate knowledge about the natural history of aging could however have several payoffs. This knowledge could unveil lineages with dated genetic hardware, possibly maladapted to current environmental challenges, and also uncover "phylogenetic modules of aging," i.e., naturally evolved pathways associated with aging or longevity from a single ancestry, with translational interest for anti-aging therapies. Here, we approximated the natural history of the genetic hardware of aging for five model fungal and animal species. We propose a lower-bound estimate of the phylogenetic age of origination for their protein-encoding gene families and protein-protein interactions. Most aging-associated gene families are hundreds of million years old, older than the other gene families from these genomes. Moreover, we observed a form of punctuated evolution of the aging hardware in all species, as aging-associated families born at specific phylogenetic times accumulate preferentially in genomes. Most protein-protein interactions between aging genes are also old, and old aging-associated proteins showed a reduced potential to contribute to novel interactions associated with aging, suggesting that aging networks are at risk of losing in evolvability over long evolutionary periods. Finally, due to reshuffling events, aging networks presented a very limited phylogenetic structure that challenges the detection of "maladaptive" or "adaptative" phylogenetic modules of aging in present-day genomes.

Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations.

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.

Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis.

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.

What doesn't kill you makes you stronger? Effects of paternal age at conception on fathers and sons.

Advancing male age is often hypothesised 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 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 Role of Selection and Migration in the Evolution of (Auto)Immunity Genes.

The genetic architecture of multiple sclerosis is complicated. Additionally, the disease incidence varies per population or per geographical region. A recent study gives convincing explanations about the north-south incidence gradient of multiple sclerosis in Europe, by analyzing ancient and modern human genomes. Interestingly, the evidence shows that multiple sclerosis associated immunogenetic variants underwent positive selection in Asian and European populations. Lifestyle and pathogen infections probably shaped the overall multiple sclerosis risk. These results complete the findings of previous studies that showed that a high percentage of the autoimmunity associated genetic variants are under selection pressure.

The Waxy Gene Has Pleiotropic Effects on Hot Water-Soluble and -Insoluble Amylose Contents in Rice (Oryza sativa) Grains.

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 λmax 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.

FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

AIMS: Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). Distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. Phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. METHODS AND RESULTS: Here, we show that FLT4 variants identified in TOF patients, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wildtype FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of wildtype human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. CONCLUSIONS: Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms. TRANSLATIONAL PERSPECTIVE: Proteostatic dysfunction, if confirmed as a mechanism of CHD pathogenesis for other predisposing genes, may identify pathways to therapeutic interventions. Distinguishing mechanistically how variants in FLT4 give rise to CHD may have potential to individualise genetic counselling in affected families.

shaPRS: Leveraging shared genetic effects across traits or ancestries improves accuracy of polygenic scores.

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.

Identification of superior haplotypes for flowering time in pigeonpea through candidate gene-based association study of a diverse minicore collection.

KEY MESSAGE: In current study candidate gene (261 genes) based association mapping on 144 pigeonpea accessions for flowering time and related traits and 29 MTAs producing eight superior haplotypes were identified. In the current study, we have conducted an association analysis for flowering-associated traits in a diverse pigeonpea mini-core collection comprising 144 accessions using the SNP data of 261 flowering-related genes. In total, 13,449 SNPs were detected in the current study, which ranged from 743 (ICP10228) to 1469 (ICP6668) among the individuals. The nucleotide diversity (0.28) and Watterson estimates (0.34) reflected substantial diversity, while Tajima's D (-0.70) indicated the abundance of rare alleles in the collection. A total of 29 marker trait associations (MTAs) were identified, among which 19 were unique to days to first flowering (DOF) and/or days to fifty percent flowering (DFF), 9 to plant height (PH), and 1 to determinate (Det) growth habit using 3 years of phenotypic data. Among these MTAs, six were common to DOF and/or DFF, and four were common to DOF/DFF along with the PH, reflecting their pleiotropic action. These 29 MTAs spanned 25 genes, among which 10 genes clustered in the protein-protein network analysis, indicating their concerted involvement in floral induction. Furthermore, we identified eight haplotypes, four of which regulate late flowering, while the remaining four regulate early flowering using the MTAs. Interestingly, haplotypes conferring late flowering (H001, H002, and H008) were found to be taller, while those involved in early flowering (H003) were shorter in height. The expression pattern of these genes, as inferred from the transcriptome data, also underpinned their involvement in floral induction. The haplotypes identified will be highly useful to the pigeonpea breeding community for haplotype-based breeding.

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson's disease comorbidity.

BACKGROUND: Inflammatory bowel disease (IBD) and Parkinson's disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. METHODS: We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. RESULTS: The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein-protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. CONCLUSIONS: Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.