Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

GWAS determined genetic loci associated with callus induction in oil palm tissue culture.

KEY MESSAGE: GWAS identified six loci at 25 kb downstream of WAK2, a crucial gene for cell wall and callus formation, enabling development of a SNP marker for enhanced callus induction potential. Efficient callus induction is vital for successful oil palm tissue culture, yet identifying genomic loci and markers for early detection of genotypes with high potential of callus induction remains unclear. In this study, immature male inflorescences from 198 oil palm accessions (dura, tenera and pisifera) were used as explants for tissue culture. Callus induction rates were collected at one-, two- and three-months after inoculation (C1, C2 and C3) as phenotypes. Resequencing generated 11,475,258 high quality single nucleotide polymorphisms (SNPs) as genotypes. GWAS was then performed, and correlation analysis revealed a positive association of C1 with both C2 (R = 0.81) and C3 (R = 0.50), indicating that C1 could be used as the major phenotype for callus induction rate. Therefore, only significant SNPs (P ≤ 0.05) in C1 were identified to develop markers for screening individuals with high potential of callus induction. Among 21 significant SNPs in C1, LD block analysis revealed six SNPs on chromosome 12 (Chr12) potentially linked to callus formation. Subsequently, 13 SNP markers were identified from these loci and electrophoresis results showed that marker C-12 at locus Chr12_12704856 can be used effectively to distinguish the GG allele, which showed the highest probability (69%) of callus induction. Furthermore, a rapid SNP variant detection method without electrophoresis was established via qPCR-based melting curve analysis. Our findings facilitated marker-assisted selection for specific palms with high potential of callus induction using immature male inflorescence as explant, aiding ortet palm selection in oil palm tissue culture.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors.

OBJECTIVE: Schizophrenia is associated with increased risk of cardiovascular disease (CVD), although there is variation in risk among individuals. There are indications of shared genetic etiology between schizophrenia and CVD, but the nature of the overlap remains unclear. The aim of this study was to fill this gap in knowledge. METHODS: Overlapping genetic architectures between schizophrenia and CVD risk factors were assessed by analyzing recent genome-wide association study (GWAS) results. The bivariate causal mixture model (MiXeR) was applied to estimate the number of shared variants and the conjunctional false discovery rate (conjFDR) approach was used to pinpoint specific shared loci. RESULTS: Extensive genetic overlap was found between schizophrenia and CVD risk factors, particularly smoking initiation (N=8.6K variants) and body mass index (BMI) (N=8.1K variants). Several specific shared loci were detected between schizophrenia and BMI (N=304), waist-to-hip ratio (N=193), smoking initiation (N=293), systolic (N=294) and diastolic (N=259) blood pressure, type 2 diabetes (N=147), lipids (N=471), and coronary artery disease (N=35). The schizophrenia risk loci shared with smoking initiation had mainly concordant effect directions, and the risk loci shared with BMI had mainly opposite effect directions. The overlapping loci with lipids, blood pressure, waist-to-hip ratio, type 2 diabetes, and coronary artery disease had mixed effect directions. Functional analyses implicated mapped genes that are expressed in brain tissue and immune cells. CONCLUSIONS: These findings indicate a genetic propensity to smoking and a reduced genetic risk of obesity among individuals with schizophrenia. The bidirectional effects of the shared loci with the other CVD risk factors may imply differences in genetic liability to CVD across schizophrenia subgroups, possibly underlying the variation in CVD comorbidity.

Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.

Importance: Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. Objective: To identify novel, replicable genomic risk loci for SITB. Design, Setting, and Participants: This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022. Main Outcome and Measures: SITB. Results: A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry. Conclusions and Relevance: The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

Genetic diversity fuels gene discovery for tobacco and alcohol use.

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Genome-wide association study of serum tumor markers in Southern Chinese Han population.

BACKGROUND: Serum indicators AFP, CA50, CA125, CA153, CA19-9, CEA, f-PSA, SCC-Ag have been confirmed as tumor markers (TMs). We conducted a genome-wide association study on 8 tumor markers of our 427 Han population in southern China, in order to identify genetic loci that are significantly associated with the level of 8 tumor markers. METHODS: We use Gene Titan multi-channel instrument and Axiom Analysis Suite 6.0 software for genotyping. We used IMPUTE2 software for imputation, and 1000 Genomes Project (Phase 3) was used as haplotype reference. After necessary quality control and statistical analysis, genetic loci genome-wide associated with TMs (p < 5E-8) will be identified. Finally, we selected Top SNPs (p < 5E-7) from the GWAS results for replication test. We used SPSS software to draw the distribution box plots of serum TMs under different genotypes of significant loci. RESULTS: The results showed that there were only MUC1 (mucin 1)-rs4072037 significantly genome-wide associated with CA153 (p = 1.28E-18). However, we found that a total of 30 genetic loci have a suggestively significant genome-wide association with the level of 8 serum tumor markers (p < 5E-6). Then 3 Top SNPs (p < 5E-7) were selected for replication verification. The results showed that MUC1-rs4072037 was still significantly associated with CA153 in another population (p = 3.73E-08). Comparing with the TT genotype of rs4072037, the CA153 level was higher under CC or CT genotype of rs4072037. CONCLUSION: MUC1-rs4072037 is significantly genome-wide associated with CA153 level. There are 30 genetic loci suggestively genome-wide associated with level of tumor markers among the Han population from Southern China.

Identification of genetic risk loci and prioritization of genes and pathways for myasthenia gravis: a genome-wide association study.

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.

Identification of novel loci influencing refractive error in East Asian populations using an extreme phenotype design.

The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies (GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent (SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou (631 < -6.00D and 574 > 0.00D) and Wenzhou (593 < -6.00D and 54 > -1.75D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1q25.2 FAM163A, 10p11.22 NRP1/PRAD3, and 10p11.21 ANKRD30A/MTRNR2L7, together explaining 3.34% of SE variance. 10p11.21 is successfully replicated. The allele frequencies of all three loci show significant differences between major continental groups (P < 0.001). The SE reducing (more myopic) allele of rs10913877 (1q25.2 FAM163A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans (EAS = 0.60, EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.

Comparative analyses of responses to exogenous and endogenous antiherbivore elicitors enable a forward genetics approach to identify maize gene candidates mediating sensitivity to herbivore-associated molecular patterns.

Crop damage by herbivorous insects remains a significant contributor to annual yield reductions. Following attack, maize (Zea mays) responds to herbivore-associated molecular patterns (HAMPs) and damage-associated molecular patterns (DAMPs), activating dynamic direct and indirect antiherbivore defense responses. To define underlying signaling processes, comparative analyses between plant elicitor peptide (Pep) DAMPs and fatty acid-amino acid conjugate (FAC) HAMPs were conducted. RNA sequencing analysis of early transcriptional changes following Pep and FAC treatments revealed quantitative differences in the strength of response yet a high degree of qualitative similarity, providing evidence for shared signaling pathways. In further comparisons of FAC and Pep responses across diverse maize inbred lines, we identified Mo17 as part of a small subset of lines displaying selective FAC insensitivity. Genetic mapping for FAC sensitivity using the intermated B73 × Mo17 population identified a single locus on chromosome 4 associated with FAC sensitivity. Pursuit of multiple fine-mapping approaches further narrowed the locus to 19 candidate genes. The top candidate gene identified, termed FAC SENSITIVITY ASSOCIATED (ZmFACS), encodes a leucine-rich repeat receptor-like kinase (LRR-RLK) that belongs to the same family as a rice (Oryza sativa) receptor gene previously associated with the activation of induced responses to diverse Lepidoptera. Consistent with reduced sensitivity, ZmFACS expression was significantly lower in Mo17 as compared to B73. Transient heterologous expression of ZmFACS in Nicotiana benthamiana resulted in a significantly increased FAC-elicited response. Together, our results provide useful resources for studying early elicitor-induced antiherbivore responses in maize and approaches to discover gene candidates underlying HAMP sensitivity in grain crops.

Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression.

Genome-wide association studies (GWAS) have implicated the 1q22 gastric cancer risk locus in disease, but little is known about its underlying oncogenic functions. This study represents a systematic investigation of the biological significance and potential mechanism associated with the gastric cancer risk of SNP rs2075570(C>T) in 1q22. We identified two functional germline variations (rs2049805-C and rs2974931-G) in an active enhancer in a 64.8 kb high-linkage disequilibrium block of rs2075570. The enhancer upregulated ubiquitin associated protein 2 like (UBAP2L) gene expression over a 960 kb distance by chromatin looping. Gastric cancer tissues expressed significantly higher levels of UBAP2L than was observed in the matched noncancerous tissues, and the UBAP2L expression was negatively correlated with patient survival. Downregulation of UBAP2L inhibited the proliferation and invasion of human gastric cancer cells in vitro and in a xenograft mouse model. Notably, the two mutant variations significantly enforced the enhancer activity and UBAP2L expression. In conclusion, this study revealed two causal variations in the 1q22 region using tag-SNP rs2075570 as a genetic marker. These variations may affect the occurrence and progression of gastric cancer by reinforcing the expression of the 1q22-Enh enhancer-regulated UBAP2L target gene. IMPLICATIONS: Our study provides an important clue of how noncoding germline variations contribute to gastric cancer, which gives a novel insight into understanding the genetic mechanism of gastric cancer.

Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90-3.86 (P = 3.57*10-8 ) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55-4.09, P = 6.84*10-4 ). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09-3.39, P = 9.65*10-11 ). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.

Mapping the human genetic architecture of COVID-19.

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition.

The characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.

The Ribosomal Gene Loci-The Power behind the Throne.

Nucleoli form around actively transcribed ribosomal RNA (rRNA) genes (rDNA), and the morphology and location of nucleolus-associated genomic domains (NADs) are linked to the RNA Polymerase I (Pol I) transcription status. The number of rDNA repeats (and the proportion of actively transcribed rRNA genes) is variable between cell types, individuals and disease state. Substantial changes in nucleolar morphology and size accompanied by concomitant changes in the Pol I transcription rate have long been documented during normal cell cycle progression, development and malignant transformation. This demonstrates how dynamic the nucleolar structure can be. Here, we will discuss how the structure of the rDNA loci, the nucleolus and the rate of Pol I transcription are important for dynamic regulation of global gene expression and genome stability, e.g., through the modulation of long-range genomic interactions with the suppressive NAD environment. These observations support an emerging paradigm whereby the rDNA repeats and the nucleolus play a key regulatory role in cellular homeostasis during normal development as well as disease, independent of their role in determining ribosome capacity and cellular growth rates.

Epistatic interactions of genetic loci associated with age-related macular degeneration.

The currently largest genome-wide association study (GWAS) for age-related macular degeneration (AMD) defines disease association with genome-wide significance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD-associated variants that reveal joint effects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifically the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high-risk AMD. We identified genetic variant combinations correlating significantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defines novel targets and allows prioritizing further functional work into AMD pathobiology.

Molecular Configuration of Human Genome Neighboring Megabase-Sized Large Deletions Induced by X-Ray Irradiation.

The genomic landscape neighboring large deletions including the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus on human X chromosome in 6-thioguanine-resistant mutants originating from immortalized human fibroblast cells exposed to X rays was characterized by real-time quantitative PCR (qPCR)-based analyses. Among the 13 mutant clones with large deletions extending over several Mb, including the HPRT locus, revealed by 10 conventional sequence-tagged site (STS) markers, three clones bearing the largest deletions were selected for further qPCR analysis using another 21 STS markers and 15 newly designed PCR primer pairs. The results indicated that the major deletions were in very specific regions between the 130-Mb and 140-Mb positions containing the HPRT locus on the X chromosome and, contrary to our initial expectations, additional minor deletions were distributed in a patchwork pattern. These findings strongly indicate that the complex deletion patterns in the affected chromosome are related to the radiation track structure with spatially heterogeneous energy deposition and the specific structure of the chromatin-nuclear membrane complex. The uncovered complex deletion patterns are in agreement with the idea of complex chromatin damage, which is frequently associated with carcinogenesis.

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Novel risk factors for craniofacial microsomia and assessment of their utility in clinic diagnosis.

Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it's genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P < 5 × 10-8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P = 7.22 × 10-58, odds ratio = 3.15, 95% confidence interval (CI) 2.74-3.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father's smoking increases CFM risk as evidenced by interaction parameter of -0.324 (95% CI -0.578 to -0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father's smoking is a key environmental risk factor for CFM through interacting with genetic factors.