Candidate Loci Research Articles

A genome-wide association study in Swedish colorectal cancer patients with gastric- and prostate cancer in relatives.

A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer. The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model.Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study. Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between1.71-3.62 and p-values < 5 × 10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case-control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer.

Genome-Wide Selection Signals Reveal Candidate Genes Associated with Plateau Adaptation in Tibetan Sheep

Tibetan sheep have developed unique adaptations for survival in the Qinghai–Tibet Plateau environment. However, the functional genes and molecular mechanisms that regulate hypoxia adaptation have not been fully characterized. In this study, based on the whole-genome resequencing data for Tibetan sheep at different altitudes, the population differentiation index (FST) and nucleotide diversity ratio (θπ ratio) were evaluated in populations of 20 Oula sheep (3501 m altitude, OL), 20 Zashijia sheep (4369 m altitude, ZSJ), and 20 Awang sheep (4643 m altitude, AW) to reveal candidate loci related to high-altitude hypoxia. We screened 728 and 524 candidate genes in the AW vs. OL and ZSJ vs. OL groups, respectively, of which 134 genes were jointly screened. Candidate genes were mainly enriched in the Ras, melanoma, melanogenesis, VEGF, and PPAR signaling pathways. HIF1AN, PDGFA, PDGFD, ANXA2, SOCS2, NOXA1, WNT7B, MMP14, GNG2, ATF6, PGAM2, PPP3R1, GSTCD, and PPARA may play important roles in the high-altitude adaptation of Tibetan sheep. In conclusion, this study provides valuable insights into the genes and molecular mechanisms that underlie high-altitude hypoxia adaptation in Tibetan sheep.

Germline copy number variants and endometrial cancer risk.

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

Transcriptome‐Wide Association Analysis of Flavonoid Biosynthesis Genes and Their Correlation With Leaf Phenotypes in Hawk Tea (Litsea coreana var. sinensis)

ABSTRACTHawk tea (Litsea coreana var. sinensis), derived from the tender shoots or leaves, rich in flavonoids can promote healthcare for humans. The primary flavonoid are kaempferol‐3‐O‐β‐D‐glucoside, kaempferol‐3‐O‐β‐D‐galactoside, quercetin‐3‐O‐β‐D‐glucoside, and quercetin‐3‐O‐β‐D‐galactoside. The existence of an association between leaf phenotype and flavonoid content, along with the underlying mechanisms of flavonoid biosynthesis, remains incompletely understood. In this study, 109 samples were analyzed to determine the correlation and genetic variability in leaf phenotype and flavonoid content. Furthermore, a transcriptome‐wide association study identified candidate loci implicated in the biosynthesis of four key flavonoids. The study revealed that genetic variability in leaf traits and flavonoid concentrations is predominantly attributed to interpopulation differences. Flavonoid accumulation was significantly correlated with tree DBH, indicative of age‐related traits. Transcriptome‐wide association analysis identified 84 significant SNPs associated with flavonoid content, with only 13 located within gene regions. The majority of these genes are implicated in metabolic processes and secondary metabolite biosynthesis. Notably, structural genes within these regions are directly involved in pathways known to regulate flavonoid metabolism, exerting a pivotal influence on flavonoid biosynthesis. These results revealed the physiological basis for the regulation of flavonoid content, as well as the molecular mechanisms for the biosynthesis of flavonoids in hawk tea. It also lays theoretical groundwork for subsequent explorations into the genetic determinants influencing flavonoid accumulation of hawk tea.

Intraspecific diversity is critical to population-level risk assessments

Environmental risk assessment (ERA) is critical for protecting life by predicting population responses to contaminants. However, routine toxicity testing often examines only one genotype from surrogate species, potentially leading to inaccurate risk assessments, as natural populations typically consist of genetically diverse individuals. To evaluate the importance of intraspecific variation in translating toxicity testing to natural populations, we quantified the magnitude of phenotypic variation between 20 Daphnia magna clones exposed to two levels of microcystins, a cosmopolitan cyanobacterial toxin. We observed significant genetic variation in survival, growth, and reproduction, which increased under microcystins exposure. Simulations of survival showed that using a single genotype for toxicity tolerance estimates on average failed to produce accurate predictions within the 95% confidence interval over half of the time. Whole genome sequencing of the 20 clones tested for correlations between toxicological responses and genomic divergence, including candidate loci from prior gene expression studies. We found no overall correlations, indicating that clonal variation, rather than variation at candidate genes, predicts population-level responses to toxins. These results highlight the importance of incorporating broad intraspecific genetic variation, without focusing specifically on variation in candidate genes, into ERAs to more reliably predict how local populations will respond to contaminants.

Identification of significant SNPs and candidate loci for blast disease resistance via GWAS and population structure analysis in ARC panel of Oryza sativa

Identification of significant SNPs and candidate loci for blast disease resistance via GWAS and population structure analysis in ARC panel of Oryza sativa

Identification of quantitative trait locus and positional candidate loci influencing chicken egg quality under tropical conditions.

Egg quality is a vital factor in the poultry industry. High-quality eggs not only meet consumer expectations for appearance, taste, and nutritional value but also have high marketability, profitability, and consumer satisfaction. Accordingly, we executed our research with the purpose of determining chromosomal regions and genetic markers associated with egg quality in an F2 cross-bred chicken population under tropical conditions; we determined these through a genome-wide association study and quantitative trait locus (QTL) mapping. This population was created by cross-breeding the L2 line of Taiwan Country chickens, which is adapted to local conditions in Taiwan, with an experimental line (R-line) of Rhode Island Red layer chickens, which was developed by the French National Research Institute for Agriculture, Food and the Environment. A 60K single nucleotide polymorphism (SNP) genotyping array for chickens was employed to execute the analysis. Our analysis revealed 40 QTLs associated with egg quality under tropical conditions, namely 20 QTLs with genome-wide statistical significance and 20 QTLs with chromosome-wide statistical significance. Furthermore, we identified 93 SNPs exerting discernible effects on egg quality, with 10 of these effects exhibiting genome-wide significance and 83 exhibiting potential significance. The majority of the detected QTL regions and SNPs agreed with those identified as having an association with egg quality or production traits in previous studies, thus supporting the interrelationships determined between the studied characteristics. The findings of this study enhance the understanding regarding the genetic regulation governing chicken egg quality, thereby serving as a valuable reference for future functional investigations.

Discovering Novel Loci of Chronic Kidney Disease via Principal Component Analysis-Based Multiple-Trait Genome-Wide Association Study

Plain Language SummaryGenome-wide association studies (GWASs) of chronic kidney disease (CKD) traits have been widely performed, but a comprehensive approach of integrating these individual traits is lacking. We applied principal component analysis to obtain principal components (PC) of albuminuria, estimated glomerular filtration rate (eGFR), and eGFR slope from Taiwan Biobank. Using these PCs as pseudotraits, we performed the first PC-based GWAS for evaluating genetic factors associated with CKD and twenty novel candidate loci associated with CKD were found. Our results provided new understanding of possible common pathogeneses for CKD.

Genetic association study of preterm birth and gestational age in a population-based case-control study in Peru.

Preterm birth (PTB) affects ∼15 million pregnancies worldwide. Genetic studies have identified several candidate loci for PTB, but results remain inconclusive and limited to European populations. Thus, we conducted a genome-wide association study (GWAS) of PTB and gestational age at delivery (GA) among 2,212 Peruvian women. PTB cases delivered≥20 weeks' but < 37 weeks' gestation, while controls delivered at term (≥37 weeks but <42 weeks). Multivariable regressions were used to identify genetic markers for PTB and GA (∼6 million SNPs), adjusting for maternal age and the first two genetic principal components. In silico functional analysis was conducted among top signals detected with an arbitrary P < 1.0×10-5. We sought to replicate genetic markers for PTB and GA identified in Europeans, and we developed a genetic risk score for GA based on European markers. Mean GA was 30 ± 4 weeks in PTB cases (N = 933) and 39 ± 1 in the controls (N = 1,279). No associatiosn were identified at genome-wide level. Nominal PTB variants were enriched for biological pathways associated with polyketide, progesterone, steroid hormones, and glycosyl metabolism. Nominal GA variants were enriched in intronic regions and cancer pathways. Variants in WNT4 associated with GA in Europeans were replicated in our study. A genetic risk score was associated with a 2-day longer GA (P = 0.002) in our sample. This study identified various signals suggestively associated with PTB and GA in pregnant Peruvian women. None of these variants overlapped with signals previously identified in Europeans.

Sex-specific Genetic Determinants of Right Ventricular Structure and Function.

While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation. RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK NIHR BioResource Rare Diseases study. Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function and sex hormone levels. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men, and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in BMPR1A and a locus for RV end-systolic volume near DMRT2. Epigenetic data in RV tissue indicate that variation at the BMPR1A locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size 0.16 l/min/m2), despite similar RV afterload. BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.

Genomic Sequencing to Detect Cross-Breeding Quality in Dogs: An Example Studying Disorders in Sexual Development.

Disorders of sexual development (DSDs) in dogs, similar to humans, arise from genetic mutations, gonadal differentiation, or phenotypic sex development. The French Bulldog, a breed that has seen a surge in popularity and demand, has also shown a marked increase in DSD incidence. This study aims to characterize the genetic underpinnings of DSDs in a French Bulldog named Brutus, exhibiting ambiguous genitalia and internal sexual anatomy, and to explore the impact of breeding practices on genetic diversity within the breed. We utilized a comprehensive approach combining conventional cytogenetics, molecular techniques, and deep sequencing to investigate the genetic profile of Brutus. The sequence data were compared to three other male French Bulldogs' genome sequences with typical reproductive anatomy, including Brutus's father and the canine reference genome (CanFam6). We found a Robertsonian fusion involving chromosome 23 previously reported in dogs as a causative mutation responsible for sex reversal syndrome. Our findings revealed a 22% mosaicism (78,XX/77,XX), the absence of the sex-determining region (SRY) gene, and the presence of 43 unique Single Nucleotide Variants (SNVs) not inherited from the father. Notably, the run of homozygosity (ROH) analysis showed Brutus has a higher number of homozygous segments compared to other Bulldogs, with a total length of these fragments 50% greater than the average, strongly suggesting this dog is the product of the mating between siblings. Although no direct causative genes for the DSD phenotype were identified, four candidate loci warrant further investigation. Our study highlighted the need for a better annotated and curated reference dog genome to define genes causative of any specific phenotype, suggests a potential genetic basis for the DSD phenotype in dogs, and underscores the consequences of uncontrolled breeding practices in French Bulldogs. These findings highlight the importance of implementing strategic genetic management to preserve genetic health and diversity in canine populations.

A genome-wide gene-environmental interaction study identified novel loci for the relationship between ambient air pollution exposure and depression, anxiety

BackgroundGenetic factors and environmental exposures, including air pollution, contribute to the risk of depression and anxiety. While the association between air pollution and depression and anxiety has been established in the UK Biobank, there has been limited research exploring this relationship from a genetic perspective. MethodsBased on individual genotypic and phenotypic data from a cohort of 104,385 participants in the UK Biobank, a polygenic risk score for depression and anxiety was constructed to explore the joint effects of nitric oxide (NO), nitrogen dioxide (NO2), particulate matter (PM) with a diameter of ⩽2.5 μm (PM2.5) and 2.5–10 μm (PMcoarse) with depression and anxiety by linear and logistic regression models. Subsequently, a genome-wide gene-environmental interaction study (GWEIS) was performed using PLINK 2.0 to identify the genes interacting with air pollution for depression and anxiety. ResultsA substantial risk of depression and anxiety development was detected in participants exposed to the high air pollution concomitantly with high genetic risk. GWEIS identified 166, 23, 18, and 164 significant candidate loci interacting with NO, NO2, PM2.5, and PMcoarse for Patient Health Questionnaire-9 (PHQ-9) score, and detected 44, 10, 10, and 114 candidate loci associated with NO, NO2, PM2.5, and PMcoarse for General Anxiety Disorder (GAD-7) score, respectively. And some significant genes overlapped among four air pollutants, like TSN (rs184699498, PNO2 = 3.47 × 10−9; rs139212326, PPM2.5 = 1.51 × 10−8) and HSP90AB7P(rs150987455, PNO2 = 1.63 × 10−11; rs150987455, PPM2.5 = 7.64 × 10−11), which were common genes affecting PHQ-9 score for both NO2 and PM2.5. ConclusionOur study identified the joint effects of air pollution with genetic susceptibility on the risk of depression and anxiety, and provided several novel candidate genes for the interaction, contributing to an understanding of the genetic architecture of depression and anxiety.

Genome Wide Association Study Identifies Candidate Loci or Genes Responsible for Bacterial Stalk Rot Resistance in Maize

Genome Wide Association Study Identifies Candidate Loci or Genes Responsible for Bacterial Stalk Rot Resistance in Maize

Population genomic structure of the sea urchin Diadema africanum, a relevant species in the rocky reef systems across the Macaronesian archipelagos

The sea urchin Diadema africanum is a macro-herbivore found in the rocky reef systems of the West African region and Macaronesian archipelagos. Over several decades, high densities of this species have generated marine barrens in certain areas at the Canary Islands. In contrast, more recently, during the last few years, the species has suffered mass mortality events that continue to the present day. In this study, we used 9,109 Single Nucleotide Polymorphisms (SNPs) and a fragment of a mitochondrial gene to evaluate the species’ population structure, effects of mass mortalities on its diversity, and potential local adaptation across the Canary Islands and Cabo Verde. Our research provides compelling evidence of low genomic diversity and homogeneity across the studied area for neutral markers, along with recent demographic fluctuations. The high connectivity among distant areas likely allows a rapid recovering of the populations from local mortality events. Interestingly, we also observed genomic sub-structure from 405 SNPs identified as candidate loci under selection for seawater temperature. The lack of divergence among distant sites and the low diversity found can be attributed to the species’ divergence from a small ancestral genomic pool, followed by a contemporary demographic expansion, and ongoinggene flow.

Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment

BackgroundTreatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively.ResultsWe identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10−7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10−6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively.ConclusionsWe report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

Genome-wide association analysis reveals novel candidate loci and a gene regulating tiller number in orchardgrass

Tillers are specialized lateral shoots arising from axillary buds at basal nodes, and are also an important agronomic trait that determines the aboveground biomass and grain yield of various gramineous crops. So far, few genes have been reported to control tiller formation and most have been in the annual crop rice (Oryza sativa). Orchardgrass (Dactylis glomerata) is an important perennial forage crop with great economic and ecological value, but its genes regulating tillering have remained largely unknown. In the present study, we used a natural population of 264 global orchardgrass germplasms to determine genes associated with quantitative variation in tiller number through genome-wide association study analysis. A total of 19 putative loci and 55 genes associated with tiller number were thus identified. Additionally, 26 putative differentially expressed genes with tiller number, including DgCYC-C1, were identified by RNA-seq and genome-wide association study analysis. DgCYC-C1 which is involved in cell division, was overexpressed, revealing that DgCYC-C1 positively regulates tiller number. These results provide some new candidate genes or loci for the improvement of tiller number in crops, which might advance new sustainable strategies to meet global crop production challenges.

Spatially heterogeneous selection and inter-varietal differentiation maintain population structure and local adaptation in a widespread conifer

BackgroundDouglas-fir (Pseudotsuga menziesii [Mirb.] Franco) plays a critical role in the ecology and economy of Western North America. This conifer species comprises two distinct varieties: the coastal variety (var. menziesii) along the Pacific coast, and the interior variety (var. glauca) spanning the Rocky Mountains into Mexico, with instances of inter-varietal hybridization in Washington and British Columbia. Recent investigations have focused on assessing environmental pressures shaping Douglas-fir’s genomic variation for a better understanding of its evolutionary and adaptive responses. Here, we characterize range-wide population structure, estimate inter-varietal hybridization levels, identify candidate loci for climate adaptation, and forecast shifts in species and variety distribution under future climates.ResultsUsing a custom SNP-array, we genotyped 540 trees revealing four distinct clusters with asymmetric admixture patterns in the hybridization zone. Higher genetic diversity observed in coastal and hybrid populations contrasts with lower diversity in inland populations of the southern Rockies and Mexico, exhibiting a significant isolation by distance pattern, with less marked but still significant isolation by environment. For both varieties, we identified candidate loci associated with local adaptation, with hundreds of genes linked to processes such as stimulus response, reactions to chemical compounds, and metabolic functions. Ecological niche modeling revealed contrasting potential distribution shifts among the varieties in the coming decades, with interior populations projected to lose habitat and become more vulnerable, while coastal populations are expected to gain suitable areas.ConclusionsOverall, our findings provide crucial insights into the population structure and adaptive potential of Douglas-fir, with the coastal variety being the most likely to preserve its evolutionary path throughout the present century, which carry implications for the conservation and management of this species across their range.

Immune targets for schistosomiasis control identified by a genome-wide association study of East African snail vectors.

Schistosomiasis, afflicting >260 million people worldwide, could be controlled by preventing infection of freshwater snail vectors. Intestinal schistosomiasis, caused by Schistosoma mansoni, occurs predominantly in Sub-Saharan Africa and is vectored by Biomphalaria sudanica and related Biomphalaria species. Despite their importance in transmission, very little genomic work has been initiated in African snails, thus hindering development of novel control strategies. To identify genetic factors influencing snail resistance to schistosomes, we performed a pooled genome-wide association study (pooled-GWAS) on the offspring of B. sudanica collected from a persistent hotspot of schistosomiasis in Lake Victoria, Kenya, and exposed to sympatric S. mansoni. Results of the pooled-GWAS were used to develop an amplicon panel to validate candidate loci by genotyping individual snails. This validation revealed two previously uncharacterized, evolutionarily dynamic regions, SudRes1 and SudRes2, that were significantly associated with resistance. SudRes1 includes receptor-like protein tyrosine phosphatases and SudRes2 includes a class of leucine-rich repeat-containing G-protein coupled receptors, both comprising diverse extracellular binding domains, suggesting roles in pathogen recognition. No loci previously tied to schistosome resistance in other snail species showed any association with compatibility suggesting that loci involved in the resistance of African vectors differ from those of neotropical vectors. Beyond these two loci, snail ancestry was strongly correlated with schistosome compatibility, indicating the importance of population structure on transmission dynamics and infection risk. These results provide the first detail of the innate immune system of the major schistosome vector, B. sudanica, informing future studies aimed at predicting and manipulating vector competence.

Genome-Wide Association Analysis Identifies LILRB2 Gene for Pathological Myopia.

Pathological myopia (PM) is one of the leading causes of blindness, especially in Asia. To identify the genetic risk factors of PM, a two-stage genome-wide association study (GWAS) and replication analysis in East Asian populations is conducted. The analysis identified LILRB2 in 19q13.42 as a new candidate locus for PM. The increased protein expression of LILRB2/Pirb (mouse orthologous protein) in PM patients and myopia mouse models is validated. It is further revealed that the increase in LILRB2/Pirb promoted fatty acid synthesis and lipid accumulation, leading to the destruction of choroidal function and the development of PM. This study revealed the association between LILRB2 and PM, uncovering the molecular mechanism of lipid metabolism disorders leading to the pathogenesis of PM due to LILRB2 upregulation.

The past, the recent, and the ongoing evolutionary processes of the worldwide invasive ascidian Styela plicata.

Invasive species are one of the main threats to global biodiversity and, within marine ecosystems, tunicates feature some prominent examples. Styela plicata is an ascidian species inhabiting harbours in all temperate oceans and seas, thus being considered a thriving invasive species. However, this species' adaptive mechanisms, introduction history, and population structure have never been completely elucidated. Here, by genotyping 87 S. plicata individuals from 18 localities worldwide with 2b-RADseq, we confirm the global presence of four chromosome inversions, demonstrate population structuring on this species, detect local adaptation signals, and infer historical demographic events. We show that North Carolina individuals constitute an unrelated population, Atlanto-Mediterranean and Pacific localities form their own genetic clusters with substructuring, being the most evident the split between northern and southern Atlantic localities. The locality of South Carolina presents an intermediate genetic position between North Carolina and the other two groups pointing to a hybrid origin with recurrent gene flow. We generate and test demographic models, providing evidence of two independent introduction events to the Atlantic and Pacific, and an admixture that originated the population of South Carolina. Finally, we identify candidate loci for adaptation, with functions involved with cell processes, metabolism, development, and ion transport, among others. Overall, this study highlights the complex historical processes of S. plicata, which have led this species to its current distribution, population structure, and local adaptation footprint in oceans worldwide.