Genetic Susceptibility Loci Research Articles

Functional and Practical Insights Into the Genetic Basis of Takayasu Arteritis.

Takayasu arteritis (TAK) is a rare vasculitis characterized by inflammation of large arteries. Although the exact etiology of TAK remains unclear, a genetic predisposition to the disease has been established. Large-scale genetic studies have significantly contributed to the identification of genetic variation associated with immune-mediated diseases. To date, five genome-wide association studies (GWAS) have been performed in TAK, identifying multiple genetic susceptibility loci across the genome. Here, we summarize the major findings from GWAS in TAK and provide an in silico functional evaluation of the associated loci (P < 5 × 10-8) and variants in high linkage disequilibrium with them (r2 > 0.8). By exploring gene expression and chromatin interaction data, we identified candidate causal genes in TAK, some of them with well-known functional implications. The analysis of transcription factor motifs within TAK-associated loci revealed enrichment of the STAT and RUNX families, both characterized by their role in immune functions and inflammatory responses. The enrichment in biological processes in susceptibility loci confirmed the involvement of specific immune-related pathways in TAK. Further, we devised and calculated a cumulative genetic risk score for TAK and confirmed differences in genetic risk for the disease among ancestries. Finally, we provide a practical guide to communicate genetic information for TAK to patients and families.

Common Hyperglycemia Susceptibility Loci in Metabolic Syndrome Patients from Karachi, Pakistan: A Cross Sectional Study

Background: More than 75 genetic susceptibility loci have been implicated with hyperglycemia. SNPs in genes linked with satiety, insulin sensitivity, BMR (Adiponectin, FTO, and MC4R), and inflammation and autoimmunity (TNF-a) have been shown to have a relationship with metabolic syndrome. Objectives: To measure the frequency of ADIPOQ, FTO, MCR4, and TNF SNPs in metabolic syndrome patients and controls, and to assess the association of these with hyperglycemia and adiposity status. Methods: A cross-sectional study was conducted. Baseline investigations including lipid profiles, blood glucose levels, and BMI calculation were conducted for n=113 Metabolic Syndrome and n=47 healthy controls. Tetra ARMS PCR and gel electrophoresis were conducted for Adiponectin rs266729, Adiponectin rs1501299, FTO rs9939609, MCR4 rs1297013, and TNF rs1800629. Statistical analysis was performed using SPSS version 26. Results: Difference was observed in lipid profiles (including LDL, triglycerides, and cholesterol but not HDL), body fat percentage (p= 0.034), and both fasting (p=0.000) and random (p=0.000) blood glucose levels among metabolic syndrome patients versus controls. Adiponectin rs1501299, FTO rs9939609, and MCR4 rs1297013 showed genotype frequency differences between groups. Spearman’s correlation was applied to test any association of risk allele with study variables and MCR4 rs1297013 showed an independent association with Fasting Blood Glucose Level (r=0.238; p=0.024) irrespective of age, weight, or gender. Conclusion: MCR4 rs1297013 polymorphism is an independent risk factor leading to hyperglycemia in the study population, however, no other SNPs were identified to carry a significant risk. Large-scale genome-wide studies are required to identify the unique set of risk genes for the Pakistani population

Amniotic fluid modifies esophageal epithelium differentiation and inflammatory responses.

The interplay between genetic and environmental factors during pregnancy can predispose to inflammatory diseases postnatally, including eosinophilic esophagitis (EoE), a chronic allergic disease triggered by food. Herein, we examined the effects of amniotic fluid (AF) on esophageal epithelial differentiation and responsiveness to proallergic stimuli. Multiplex analysis of AF revealed the expression of 66 cytokines, whereas five cytokines including IL-4 and thymic stromal lymphopoietin (TSLP) were not detected. Several proinflammatory cytokines including TNFα and IL-12 were highly expressed in the AF from women who underwent preterm birth, whereas EGF was the highest in term birth samples. Exposure of esophageal epithelial cells to AF resulted in transient phosphorylation of ERK1/2 and the transcription of early response genes, highlighting the direct impact of AF on esophageal epithelial cells. In a three-dimensional spheroid model, AF modified the esophageal epithelial differentiation program and enhanced the transcription of IL-13-target genes, including CCL26 and CAPN14, which encodes for a major genetic susceptibility locus for eosinophilic esophagitis. Notably, CAPN14 exhibited upregulation in spheroids exposed to preterm but not term AF following differentiation. Collectively, our findings call attention to the role of AF as a potential mediator of the intrauterine environment that influences subsequent esophageal disorders.NEW & NOTEWORTHY The interaction between amniotic fluid and the esophageal epithelium during pregnancy modifies esophageal epithelial differentiation and subsequent responsiveness to inflammatory stimuli, including interleukin 13 (IL-13). This interaction may predispose individuals to inflammatory conditions of the esophagus, such as eosinophilic esophagitis (EoE), in later stages of life.

A Genome-Wide Association Study Suggests New Susceptibility Loci for Primary Antiphospholipid Syndrome.

Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS. We performed a genome-wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta-analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune-mediated diseases. We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA-DRA and in STAT1-STAT4 with a genome-wide level of significance; 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele near HLA-DRA is associated with overexpression of HLA-DRB6, HLA-DRB9, HLA-DQA2, and HLA-DQB2 in immune cells, vascular tissue, and nervous tissue. This association is independent of the association between PAPS and HLA-DRB1*1302. Functional analyses highlighted immune-related pathways in PAPS-associated loci. The comparison with other immune-mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren syndrome, suggesting co-localized causal variations close to STAT1-STAT4, TNPO3, and BLK. This study represents a comprehensive large-scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease.

Pediatric Chordoma: A Tale of Two Genomes.

Little is known about the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed WES and mtDNA genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole-genome sequencing datasets of 80 adult patients with skull base chordoma. In the pediatric chordoma cohort, 81% of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared with the rest of the mtDNA genes (P = 0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (P < 0.0001). Furthermore, a progressive increase in heteroplasmy of nonsynonymous mtDNA mutations was noted in patients with multiple tumors (P = 0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that in the adult cohort (P = 0.0236, Fisher's exact test), but they were both significantly higher than that in the ethnicity-matched populations (P < 5.9e-07 and P < 0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations seem important for chordoma genesis, especially in pediatric chordoma.

Decoding the genetic landscape of juvenile dermatomyositis: insights from phosphorylation-associated single nucleotide polymorphisms.

Genome-wide association studies (GWASs) have identified genetic susceptibility loci associated with juvenile dermatomyositis (JDM). Single nucleotide polymorphisms related to phosphorylation (phosSNPs) are critical nonsynonymous mutations exerting substantial influence on gene expression regulation. The aim of this study was to identify JDM susceptibility genes in the GWAS loci by the use of phosSNPs. We explored quantitative trait loci (QTLs) among the phosSNPs associated with JDM using data from eQTL (bulk tissues and single-cell) and pQTL studies. For gene expression and protein levels significantly influenced by JDM-associated phosSNPs, we assessed their associations with JDM through MR analyses. Additionally, we conducted differential expression gene analyses, incorporating single-cell transcriptomic profiling of 6 JDM cases and 11 juvenile controls (99,396 cells). We identified 31 phosSNPs situated in the 6p21 locus that were associated with JDM. Half of these phosSNPs showed effects on gene expression in various cells and circulating protein levels. In MR analyses, we established associations between the expression levels of pivotal JDM-associated genes, including MICB, C4A, HLA-DRB1, HLA-DRB5, and PSMB9, in skin, muscle, or blood cells and circulating levels of C4A, with JDM. Utilizing single-cell eQTL data, we identified a total of 276 association signals across 14 distinct immune cell types for 28 phosSNPs. Further insights were gained through single-cell differential expression analysis, revealing differential expression of PSMB9, HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1 in immune cells. The present study pinpointed phosSNPs within susceptibility genes for JDM and unraveled the intricate relationships among these SNPs, gene expression levels, and JDM.

Multimorbidity in Severe Mental Illness as Part of the Neurodevelopmental Continuum: Physical Health-Related Endophenotypes of Schizophrenia-A Narrative Review.

The majority of deaths in patients with schizophrenia and other severe mental illnesses (SMIs) are caused by natural causes, such as cardiovascular diseases (CVDs). The increased risk of CVD and other somatic diseases in SMIs cannot be fully explained by the contribution of traditional risk factors, behavioral risk factors, patients' lifestyle peculiarities, and the influence of antipsychotics. The present review has the following main objectives: (1) to aggregate evidence that neurodevelopmental disorders are the basis of SMIs; (2) to provide a review of studies that have addressed the shared genetic architecture of SMI and cardiovascular disease; and (3) to propose and substantiate the consideration of somatic diseases as independent endophenotypes of SMIs, which will make it possible to place the research of somatic diseases in SMIs within the framework of the concepts of the "neurodevelopmental continuum and gradient" and "endophenotype". A comprehensive literature search was performed on 1 July 2024. The search was performed using PubMed and Google Scholar databases up to June 2024. The current literature reveals considerable overlap between the genetic susceptibility loci for SMIs and CVDs. We propose that somatic diseases observed in SMIs that have a shared genetic architecture with SMIs can be considered distinct physical health-related endophenotypes. In this narrative review, the results of recent studies of CVDs in SMIs are summarized. Reframing schizophrenia as a multisystem disease should contribute to the activation of new research on somatic diseases in SMIs.

Genetic factors contributing to the development of inguinal hernias – a narrative review

Introduction and aim. Inguinal hernias are one of the major disorders in the field of general and visceral surgery and can be viewed as multifactorial diseases. Although the molecular mechanism that led to predistortion to inguinal herniation still remain unclear, is well known that defects leading to improper closure of the inguinal canal during fetal development and mechanisms contributing to weaker muscles of the abdominal wall can greatly increase the risk of developing the latter disease. Material and methods. A literature search was performed in all major electronic databases using keywords and Boolean operators to retrieve all available literature related to the topic. Due to the narrative nature of the review, there were no specific inclusion and exclusion criteria. Analysis of the literature. Genetic factors, undoubtedly, can interfere with these mechanisms and therefore play major role in developing hernias. To this end, the present narrative review provides an overview of genes with altered expression and genetic polymorphisms associated with inguinal herniation. Moreover, the results of genome-wide association studies (GWAS) exploring susceptible genetic loci associated with the disease have been reported. Conclusion. Nevertheless, more case-control studies and GWAS need to be conducted in different ethnic populations so as to provide better insights into the topic.

Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci.

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

Identification of novel genetic susceptibility loci for calcium-containing kidney stone disease by genome-wide association study and polygenic risk score in a Taiwanese population.

Approximately 80% of kidney stone diseases contain calcium. Inherited genetic factors are among the variables that influence the development of calcium-containing kidney stone diseases (CKSD). Previous genome-wide association studies (GWAS) on stone diseases have been reported worldwide; however, these are not focused on calcium-containing stones. We conducted a GWAS to identify germline genetic polymorphisms associated with CKSD in a Medical Center in Taiwan; hence, this study was based primarily on a hospital-based database. CKSD was diagnosed using the chart records. Patients infected with urea-splitting-microorganisms and those with at least two urinary pH value below 5.5 were excluded. None of the patients had cystic stones based on stone analysis. Those over 40 years of age with no history of CKSD and no microscopic hematuria on urinalysis were considered as controls. The DNA isolated from the blood of 14,934 patients (63.7% male and 36.3% female) with CKSD and 29,868 controls (10,830 men and 19,038 women) at a medical center was genotyped for approximately 714,457 single nucleotide polymorphisms (SNPs) with minor allele frequency of ≥ 0.05. We used PLINK 1.9 to calculate the polygenic risk score (PRS) to investigate the association between CKSD and controls. The accuracy of the PRS was verified by dividing it into the training and testing groups. The statistical analyses were calculated with the area under the curve (AUC) using IBM SPSS version 22. We identified 432 susceptibility loci that reached a genome-wide threshold of P < 1.0 × 10- 5. A total of 132 SNPs reached a threshold of P < 5 × 10- 8 using a stricter definition of significance on chromosomes 4, 13, 16, 17, and 18. At the top locus of our study, SNPs in DGKH, PDILT, BCAS3, and ABCG2 have been previously reported. RN7SKP27, HDAC4, PCDH15, AP003068.2, and NFATC1 were novel findings in this study. PRS was adjusted for sex and age, resulting in an AUC of 0.65. The number of patients in the top quartile of PRS was 1.39 folds in the risk of CKSD than patients in the bottom quartile. Our data identified the significance of GWAS for patients with CKSD in a hospital-based study. The PRS also had a high AUC for discriminating patients with CKSD from controls. A total of 132 SNP loci of SNPs significantly associated with the development of CKSD. This first survey, which focused on patients with CKSD, will provide novel insights specific to CKSD and its potential clinical biomarkers.

Genetic studies of type 2 diabetes, and microvascular complications of diabetes.

Genome-wide association studies (GWAS) have significantly advanced the identification of genetic susceptibility variants associated with complex diseases. As of 2023, approximately 800 variants predisposing individuals to the risk of type 2 diabetes (T2D) were identified through GWAS, and the majority of studies were predominantly conducted in European populations. Despite the shared nature of the majority of genetic susceptibility loci across diverse ethnic populations, GWAS in non-European populations, including Japanese and East Asian populations, have revealed population-specific T2D loci. Currently, polygenic risk scores (PRSs), encompassing millions of associated variants, can identify individuals with a higher T2D risk than the general population. However, GWAS focusing on microvascular complications of diabetes have identified a limited number of disease-susceptibility loci. Ongoing efforts are crucial to enhance the applicability of PRS for all ethnic groups and unravel the genetic architecture of microvascular complications of diabetes.

Abstract PO4-19-02: Genetic risk estimation in breast cancer and assessing health disparities

Abstract Background: Breast Cancer (BC) incidence and the distribution of BC risk factors vary between racial and ethnic groups within the United States. It has been demonstrated that providing education on individualized breast cancer risk will improve patient uptake to recommended BC screening and prevention strategies. Most clinical risk assessment tools, including the validated IBIS model were derived from data using non-Hispanic white women. Consortia have also now identified over 300 common genetic susceptibility loci for BC, summarized by the polygenic risk score (PRS). When combined with clinical risk assessment tools, such as the IBIS or BCRAT models, the PRS can further refine risk estimation for patients. To date, most studies on the use of PRS have been done in non-Hispanic white women. While these PRS still perform well in racial minorities, there has been a recognized need to improve racial and ethnic diversity in genomic research cohorts. Herein, we aim to combine clinical risk assessment models that are already used in routine clinical practice with information derived from PRS testing in women of racial minorities to determine if this can improve risk estimation, patient understanding, and uptake to recommended breast cancer screening and prevention strategies. Design: This is a minimal risk prospective study with a single arm incorporating the PRS into a standard breast cancer risk reduction consultation, followed by annual surveys over 10 years to determine if and how the information provided by the PRS influenced patient decisions regarding recommended BC screening and prevention. Patients will have IBIS and BCRAT risks calculated at baseline visit. A survey of patient perceptions/understanding of risk, intention to undergo screening, and use of preventive medicine is completed after baseline visit prior to receiving the PRS results. Blood sample is obtained at baseline and DNA samples are analyzed for approximately 300 SNPs on a custom-designed, targeted SNP panel from ThermoFisher Scientific by the Mayo Clinic Genomics Laboratory. This PRS result is then combined with the clinical risk assessments (IBIS and BCRAT scores) using the R package Individualized Coherent Absolute Risk Estimators (iCare) tool to provide a new estimate of breast cancer risk for 5year, 10year, and lifetime risk. Patients are seen for follow-up to review results and then complete a second survey to assess their understanding of the results, BC risk, and how the PRS impacted their decision to undergo screening/prevention strategies. Eligibility Criteria: Women who self-identify as African American/Black or Hispanic/Latinx between 30-75 years old with any of the following: 1.)IBIS score of ≥5% for the 10 year risk OR BCRAT score of ≥ 3 % for the 5 year risk. 2.) History of biopsy proven atypical hyperplasia 3.) History of biopsy proven lobular carcinoma in situ. Specific Aims: Aim 1: The primary aim of this study is to explore if the addition of PRS to the BCRAT and IBIS score will improve intentions to undergo recommended breast cancer screening strategies such as mammography, MRI, or molecular breast imaging in women of underserved racial minorities Aim 2: To explore if the addition of the PRS to the BCRAT and IBIS risk score will aid women of racial minorities in deciding whether to take preventative endocrine therapy. Aim 3: To understand how individualized risk assessment and information on PRS may alter perceived risk of breast cancer. Statistical Methods Analysis will be mostly descriptive. Continuous variables will be summarized as mean (standard deviation) or median (range) and categorical variables will be reported as frequency (percentage). Kaplan-Meier method will be used to estimate the long-term cumulative risk of cancer. Current Accrual: 3. Target Accrual: 50 Citation Format: Lauren Cornell, Sandhya Pruthi, Linda Hasadsri, Sarah McLaughlin. Genetic risk estimation in breast cancer and assessing health disparities [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-02.

Antipsychotic-induced epigenomic reorganization in frontal cortex of individuals with schizophrenia

Genome-wide association studies have revealed &gt;270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.

Genetic overlap between psoriatic arthritis and ankylosing spondylitis in a Chinese population.

Previous studies reveal that psoriatic arthritis (PsA) and ankylosing spondylitis (AS) share susceptibility genes, such as HLA-B27, demonstrating a degree of genetic overlap between these diseases. Recent studies have identified a number of novel AS and PsA genetic susceptibility loci, but data on these loci in Chinese PsA patients are limited. To identify candidate genes that confer susceptibility to PsA in Chinese patients with PsA, psoriasis vulgaris (PsV), and healthy controls. Sixteen susceptibility loci, reported in a genome-wide association study of AS, and nine susceptibility loci, reported in candidate gene studies of PsA, were examined. Single-nucleotide polymorphisms (SNPs) were genotyped in 503 patients with PsA, 496 patients with PsV, and 979 healthy controls using the SNPscanTM multiplex SNP genotyping platform. PLINK software and logistic regression analysis were used to estimate the statistical significance of associations. PPP2R3C (rs8006884) was shown to significantly associate with PsA+PsV (p = 1.92×10-3, OR = 1.28) and was suggested to associate with PsV (p = 0.03, OR = 1.19). A suggestive association was also observed between IL-23R (rs12141575) and PsA as well as with axial PsA based on subtype analysis, KIF3A (rs2897442) and PsV, and ERN1 (rs196941) or IFIH1 (rs984971) and axial PsA. Our results suggest that PPP2R3C confers susceptibility to PsA and PsV, and that this gene may be related to the pathogenesis of psoriatic lesions and arthritis. Moreover, our results indicate a possible association between IL-23R, ERN1, or IFIH1 and subtypes of PsA, and between KIF3A and PsV.

Interpretation of 10years of Alzheimer's disease genetic findings in the perspective of statistical heterogeneity.

Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.

Abstract 6147: Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers

Abstract Objectives: Genetic susceptibility is thought to contribute to the development of multiple primary cancers (MPC), often called secondary cancers. Although rare variants contribute to risk, these only account for a small fraction of MPC cases. The contribution of common variants to risk is unknown. Methods: To identify common genetic variants associated with the risk of MPC, we conducted a trans-ancestry meta-analysis of genome-wide association studies (GWAS), including 7,360 MPC cases and 138,684 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and UK Biobank (UKBB). Association analyses were performed separately by genetic ancestry, genotype platform, and study, adjusting for age, sex, and principal components, and the results were meta-analyzed together using a fixed effects model. Genome-wide SNP heritability was estimated using GCTA. Pathway and functional enrichment analyses were conducted to gain insights into potential biological mechanisms underlying discovered loci. Results: We identified one novel locus at chromosome 3q26.2 (LRRC34, rs7621631) that was associated with MPC risk (P=1.16x10-8). Variants in this region have been previously associated with telomere length, suggesting a possible underlying mechanism. In sex-stratified analyses, we identified an additional locus at chromosome 12q24.33 (intergenic, rs10466868) associated with MPC in men (P= 7.76x10-8), but not women. Although the risk associated with these two discovered loci was small, the genome-wide SNP heritability was estimated to be 12%, suggesting that there are likely more common variants to be discovered for MPC risk. Conclusions: Our study demonstrates that common genetic variation contributes to the risk of multiple primary cancers and suggests additional loci are likely to be identified with larger studies. Citation Format: Shisi He, James Perry, Shengchao Li, Braxton D. Mitchell, Yuji Zhang, Shuo Chen, Laura Beane-Freeman, Kathryn Hughes Barry, Sonja I. Berndt. Genome-wide association study identifies new genetic susceptibility loci for multiple primary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6147.

Association between rs1799724 of TNF- α gene and early onset preeclampsia in Chinese: A pilot study

ObjectiveTo investigate the association between polymorphisms of TNF- α (rs1799724, rs1800629), VEGF (rs3025039) and VEGFR1 (rs 722503) and early onset preeclampsia (EOPE) in Chinese. MethodsA total of 132 EOPE patients from January 2016 to December 2018 at the Second Hospital of Tianjin Medical University were selected as the EOPE group, and 156 normal pregnant patients as the Control group. In both groups, 5 ml of peripheral venous blood was obtained after admission. The characteristics of genotype and allele distribution at the four SNPs in the study subjects were examined by matrix-assisted laser desorption ionization time-of-flight mass spectrometric genotyping. ResultsThe genotype frequency distribution and allele frequency distribution of rs1799724 were significantly different between the EOPE group and the Control group (P = 0.002，P = 0.003). The T allele was statistically associated with the development of EOPE under a dominant genetic model (P = 0.001). The genotype and allele frequency distributions of rs1800629, rs3025039, and rs 722503 did not differ significantly between the EOPE group and the Control group (P > 0.05). There was no linkage disequilibrium among rs1799724, rs1800629 and rs3025039 loci, the corresponding haploid cannot be formed. ConclusionsThe rs1799724 of TNF- α gene is a genetic susceptibility locus for EOPE and may be a potential predictors of preeclampsia.

Abstract A004: Identification of genetic susceptibility loci for ErbB2-driven mammary tumor development and metastasis using Collaborative Cross mice and human relevant validation

Abstract Introduction Epidermal growth factor receptor 2 (HER2)-targeted therapies are effective treatments for HER2+ breast cancers (BC), but intrinsic and acquired resistance hampers their clinical benefit. Therefore, new biological insights into HER2-driven cancers are needed to conquer drug resistance. Here, we used a genetically diverse and population-based Collaborative Cross (CC) mouse model to identify genetic susceptibility to tumor development and metastasis driven by HER2. Materials and methods 732 F1 hybrid mice were generated from a cross between FVB/N MMTV-ErbB2 and 30 CC strains and were monitored for mammary tumor development within two years. Tumor onset, multiplicity and metastasis were assessed. Genome wide association study (GWAS) was used to identify genetic variations controlling different tumor phenotypes. Polygenetic risk score was created for each phenotype using multivariate analysis. We systematically evaluated the clinical value regarding prognosis and therapeutic responses of mouse tumor susceptibility gene signature (mTSGS) in human breast cancer (BC) using publicly available cohorts including I-SPY2 clinical trial cohorts. Results We observed huge differences in tumor onset, multiplicities, and metastasis across 30 CC strains. In addition to lung metastasis, we found liver/kidney metastasis in some CC strains. GWAS identified 1,525 SNPs significantly associated with tumor onset (p&amp;lt;1.00E-30) corresponding to 287 known genes, 800 SNPs significantly associated with number of tumors (p&amp;lt;1.00E-15) corresponding to 203 known genes, 568 SNPs significantly associated with lung metastasis (p&amp;lt;1.00E-4) corresponding to 189 known genes, and 23 SNPs significantly associated with liver metastasis (p&amp;lt;1.00E-4) corresponding to 12 known genes. Multivariate analyses identified the SNPs in 8 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b and Rer1) independently associated with age onset, in 11 genes (Stx6, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a and Oxr1) independently associated with number of tumors, and in 2 genes (Plxna2 and Tbc1d31) independently associated with tumor metastasis, which were pooled together as mTSGS. To evaluate the impact of mTSGS on human BC, we established mTSGS score (mTSGSS) based on their transcriptional levels in BC. We found that mTSGSS is significantly and independently associated with overall, disease free and progression free survival compared to clinical factors and PAM50 molecular subtype in different cohorts. Additionally, patients with low mTSGSS have a higher pathological complete response (pCR) rate in comparison to these with high mTSGSS for 6 of 13 treatment regimens in I-SPY2 cohort. Multivariate logistic regression analysis showed that predictive value of mTSGSS in pCR is independent of MammaPrint (MP) score in these treatment regimens. Conclusion Our findings lead significantly to biological insights into ErbB2-driven cancers and indicate that mTSGSS can serve as a biomarker for tailoring treatment to BC patients. Citation Format: Hang Chang, Jamie L Inman, Antoine M Snijders, Jian-Hua Mao. Identification of genetic susceptibility loci for ErbB2-driven mammary tumor development and metastasis using Collaborative Cross mice and human relevant validation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A004.

Lymphocyte-Specific Protein 1 Regulates Expression and Stability of Endothelial Nitric Oxide Synthase.

Nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), plays a critical role in blood pressure regulation. Genome-wide association studies have identified genetic susceptibility loci for hypertension in human lymphocyte-specific protein 1 (LSP1) gene. LSP1 is recognized as modulator of leukocyte extravasation, and endothelial permeability, however, the role of LSP1 in regulation of NO signaling within endothelial cells (ECs) remains unknown. The present study investigated the role of LSP1 in the regulation of eNOS expression and activity utilizing human macrovascular ECs in vitro and LSP1 knockout (KO) mice. In ECs, specific CRISPR-Cas9 genomic editing deleted LSP1 and caused downregulation of eNOS expression. LSP1 gain-of-function through adenovirus-mediated gene transfer was associated with enhanced expression of eNOS. Co-immunoprecipitation and confocal fluorescence microscopy revealed that eNOS and LSP1 formed a protein complex under basal conditions in ECs. Furthermore, LSP1 deficiency in mice promoted significant upregulation and instability of eNOS. Utilizing a mass-spectrometry-based bottom-up proteomics approach, we identified novel truncated forms of eNOS in immunoprecipitates from LSP1 KO aortae. Our experimental data suggest an important role of endothelial LSP1 in regulation of eNOS expression and activity within human ECs and murine vascular tissues.

BioGWAS: A Simple and Flexible Tool for Simulating GWAS Datasets.

Genome-wide association studies (GWAS) have proven to be a powerful tool for the identification of genetic susceptibility loci affecting human complex traits. In addition to pinpointing individual genes involved in a particular trait, GWAS results can be used to discover relevant biological processes for these traits. The development of new tools for extracting such information from GWAS results requires large-scale datasets with known biological ground truth. Simulation of GWAS results is a powerful method that may provide such datasets and facilitate the development of new methods. In this work, we developed bioGWAS, a simple and flexible pipeline for the simulation of genotypes, phenotypes, and GWAS summary statistics. Unlike existing methods, bioGWAS can be used to generate GWAS results for simulated quantitative and binary traits with a predefined set of causal genetic variants and/or molecular pathways. We demonstrate that the proposed method can recapitulate complete GWAS datasets using a set of reported genome-wide associations. We also used our method to benchmark several tools for gene set enrichment analysis for GWAS data. Taken together, our results suggest that bioGWAS provides an important set of functionalities that would aid the development of new methods for downstream processing of GWAS results.