scholarly journals Common genetic variants shared among five major psychiatric disorders: a large-scale genome-wide combined analysis

2019 ◽  
pp. 21-30 ◽  
Author(s):  
Lu Xia ◽  
Kun Xia ◽  
Daniel Weinberger ◽  
Fengyu Zhang
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Autism Spectrum ◽  
Epigenetic Mechanism ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Childhood Disorders ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Genome Wide Significance

Background. Genetic correlation and pleiotropic effects among psychiatric disorders have been reported. This study aimed to identify specific common genetic variants shared between five adult psychiatric disorders: schizophrenia, bipolar, major depressive disorder, attention deficit-hyperactivity disorder, and autism spectrum disorder. Methods. A combined p-value of about 8 million single nucleotide polymorphisms (SNPs) was calculated in an equivalent sample of 151,672 cases and 284,444 controls of European ancestry from published data based on the latest genome-wide association studies of five major psychiatric disorder. SNPs that achieved genome-wide significance (P<5x10-08) were mapped to loci and genomic regions for further investigation; gene annotation and clustering were performed to understand the biological process and molecular function of the loci identified. We also examined CNVs and performed expression quantitative trait loci analysis for SNPs by genomic region. Results. We find that 6,293 SNPs mapped to 336 loci shared by the three adult psychiatric disorders, 1,108 variants at 73 loci shared by the childhood disorders, and 713 variants at 47 genes shared by all five disorders at genome-wide significance (P<5x10-08). Of the 2,583 SNPs at the extended major histocompatibility complex identified for three adult disorders, none of them were associated with childhood disorders; and SNPs shared by all five disorders were located in regions that have been identified as containing copy number variation associated with autism and had largely neurodevelopmental functions. Conclusion. We show a number of specific SNPs associated with psychiatric disorders of childhood or adult-onset, illustrating not only genetic heterogeneity across these disorders but also developmental genes shared by them all.  These results provide a manageable list of anchors from which to investigate epigenetic mechanism or gene-gene interaction on the development of neuropsychiatric disorders and for developing a measurement matrix for disease risk to potentially develop a novel taxonomy for precision medicine.

scholarly journals T173. POLYGENETIC RISK SCORES FOR MAJOR PSYCHIATRIC DISORDERS AMONG SCHIZOPHRENIA PATIENTS, THEIR FIRST-DEGREE RELATIVES AND HEALTHY SUBJECTS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S297-S297
Author(s):  
Kazutaka Ohi ◽  
Daisuke Nishizawa ◽  
Takamitsu Shimada ◽  
Yuzuru Kataoka ◽  
Junko Hasegawa ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Age At Onset ◽  
Japanese Patients ◽  
Autism Spectrum ◽  
European Ancestry ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
First Degree Relatives ◽  
Genome Wide

Abstract Background The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. On the other hand, these major psychiatric disorders are distinct diagnoses that have disorder-specific genetic factors. Recently, the bipolar disorder (BIP) and SCZ Working Group of the PGC identified two genome-wide significant loci differentiating the two disorders in individuals of European descent. We hypothesized that genetic variants differentiating SCZ from BIP in Europeans as well as genetic variants related to psychiatric disorders in Europeans would overlap with genetic risk variants in Japanese SCZ patients and unaffected first-degree relatives (FRs), i.e., individuals at high risk of developing SCZ. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected FRs and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. Methods To calculate PRSs for five psychiatric disorders [SCZ, BIP, major depressive disorder (MDD), autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD)] and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target subjects [131 SCZ patients, 57 of their unaffected FRs and 147 healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders (SCZ, BIP, SCZ vs BIP, MDD, ASD and ADHD) and investigated their effect on risk in Japanese SCZ patients [(i) SCZ vs FRs vs HCs, (ii) SCZ vs HCs and (iii) SCZ vs FRs] or unaffected FRs [(iv) FRs vs HCs] by PRS analyses. Results The PRSs obtained from European SCZ samples were significantly higher in Japanese patients with SCZ than in HCs [(i) SCZ vs FRs vs HCs, a maximum at PT≤1.0: adjusted R2=0.028, p=1.30×10–3; (ii) SCZ vs HCs, a maximum at PT≤1.0: Nagelkerke’s R2=0.049, p=1.66×10–3]. In addition, the PRSs related to European BIP were nominally higher in Japanese patients with SCZ than in HCs [(i) SCZ vs FRs vs HCs, a maximum at PT≤0.5: adjusted R2=0.016, p=0.012; (ii) SCZ vs HCs, a maximum at PT≤0.5: Nagelkerke’s R2=0.029, p=0.015]. Furthermore, PRSs differentiating SCZ patients from European BIP patients were marginally higher in Japanese SCZ patients than in HCs [(i) SCZ vs FRs vs HCs, a maximum at PT≤0.05: adjusted R2=0.010, p=0.043; (ii) SCZ vs HCs, a maximum at PT≤0.05: Nagelkerke’s R2=0.020, p=0.046]. Interestingly, the PRSs obtained from European ASD were marginally lower in Japanese FRs compared with HCs [(iv) FRs vs HCs, a maximum at PT≤0.01: Nagelkerke’s R2=0.045, p=0.013] and patients with SCZ [(iii) SCZ vs FRs, a maximum at PT≤0.2: Nagelkerke’s R2=0.023, p=0.084]. As childhood-onset patients with SCZ have showed higher PRSs for both SCZ and ASD than their unaffected siblings, we further investigated the correlation between age at onset and PRSs for both SCZ and ASD in our SCZ samples. Lower age at onset of SCZ was significantly associated with higher PRSs for ASD (PT≤0.05: beta=-0.20, p=7.13×10–3) but not PRSs for SCZ (p&gt;0.05). Discussion These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected FRs may help protect against SCZ development.

Abstract MP56: A Gene-centric Association Study of Activated Partial Thromoplastin Time in European Americans and African Americans: The ARIC Study

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Lu-Chen Weng ◽  
Weihong Tang ◽  
Mary Cushman ◽  
James S Pankow ◽  
Saonli Basu ◽  
...  
Keyword(s):  
African Americans ◽  
Candidate Gene ◽  
Genetic Variants ◽  
European Ancestry ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Link Type ◽  
European Americans ◽  
Common Genetic Variants ◽  
Aric Study

Introduction: Activated partial thromboplastin time (aPTT) is commonly used to screen for coagulation factor deficiencies. Shorter aPTT is also a risk marker for incident and recurrent venous thromboembolism (VTE). Genetic factors influencing aPTT are not well understood. aPTT was associated with common genetic variants of coagulation factors V (F5), XI (F11), XII (F12), KNG1, HRG, and ABO in previously reported genome-wide association studies (GWAS) that were conducted in individuals of European ancestry; no data have been reported in other race groups. Hypothesis: The present study aimed to identify aPTT-related gene variants in European Americans (EAs) and African Americans (AAs). Methods: We conducted a large-scale candidate gene study for aPTT in 9,719 EAs and 2,799 AAs from the Atherosclerosis Risk in Communities (ARIC) study. Subjects on anticoagulants were excluded. Nearly 50,000 single nucleotide polymorphisms (SNPs) located in 2,100 candidate genes were genotyped by the Candidate gene Association Resource (CARe) gene chip. The association between each SNP and aPTT was assessed with an additive genetic model using linear regression adjusted for age, sex, and field center. We additionally adjusted for principal components in AAs to account for potential population stratification. P-value for significant threshold was set at 2x10-6 after accounting for multiple testing. Results: In EAs, fifty-five SNPs from F5, HRG, KNG1, F11, F12, and ABO genes exceeded the significant p-value threshold. The signals in HRG, KNG1, F11, F12, and ABO genes replicated the previously reported GWAS findings. The top variant in F5 identified in EAs was only weakly associated with the previously reported GWAS variant (rs2239852, p=1.89x10-08 and r2=0.02 with rs9332701 reported in the previously reported GWAS). In AAs, twenty-seven SNPs from the HRG, KNG1, F12, and ABO genes were significantly associated with aPTT. The top signals from the HRG (rs9898, p=1.19x10-27) and KNG1 genes ( rs710446 , p=8.41x10-42) replicated the previously reported signals in EAs with similar effect size and direction of association, but the top signals in the F12 and ABO genes were weakly associated with the previously reported variants in EAs (rs1801020 in F12: p=1.01x10-84 and r2=0.12 with rs2545801, and rs8176722 in ABO: p=1.62x10-29 and r2=0.26 with rs687621 , respectively). Conclusions: Our study replicated the previously reported associations of aPTT with HRG, KNG1, F11, F12, and ABO genes in EAs and with HRG and KNG1 in AAs. The signals from F5 identified in EAs and from F12 and ABO identified in AAs may represent new genetic variants for aPTT.

scholarly journals Assessing the Causal Effects of Human Serum Metabolites on 5 Major Psychiatric Disorders

2020 ◽  
Vol 46 (4) ◽  
pp. 804-813 ◽  
Author(s):  
Jian Yang ◽  
Bin Yan ◽  
Binbin Zhao ◽  
Yajuan Fan ◽  
Xiaoyan He ◽  
...  
Keyword(s):  
Human Serum ◽  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Association Studies ◽  
Autism Spectrum ◽  
Causal Effects ◽  
Human Diseases ◽  
Genome Wide Association Studies ◽  
Serum Metabolites ◽  
Intermediate Phenotypes

Abstract Psychiatric disorders are the leading cause of disability worldwide while the pathogenesis remains unclear. Genome-wide association studies (GWASs) have made great achievements in detecting disease-related genetic variants. However, functional information on the underlying biological processes is often lacking. Current reports propose the use of metabolic traits as functional intermediate phenotypes (the so-called genetically determined metabotypes or GDMs) to reveal the biological mechanisms of genetics in human diseases. Here we conducted a two-sample Mendelian randomization analysis that uses GDMs to assess the causal effects of 486 human serum metabolites on 5 major psychiatric disorders, which respectively were schizophrenia (SCZ), major depression (MDD), bipolar disorder (BIP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Using genetic variants as proxies, our study has identified 137 metabolites linked to the risk of psychiatric disorders, including 2-methoxyacetaminophen sulfate, which affects SCZ (P = 1.7 × 10–5) and 1-docosahexaenoylglycerophosphocholine, which affects ADHD (P = 5.6 × 10–5). Fourteen significant metabolic pathways involved in the 5 psychiatric disorders assessed were also detected, such as glycine, serine, and threonine metabolism for SCZ (P = .0238), Aminoacyl-tRNA biosynthesis for both MDD (P = .0144) and ADHD (P = .0029). Our study provided novel insights into integrating metabolomics with genomics in order to understand the mechanisms underlying the pathogenesis of human diseases.

GWAS contribution to atrial fibrillation and atrial fibrillation-related stroke: pathophysiological implications

2019 ◽  
Vol 20 (10) ◽  
pp. 765-780 ◽  
Author(s):  
Diana Cruz ◽  
Ricardo Pinto ◽  
Margarida Freitas-Silva ◽  
José Pedro Nunes ◽  
Rui Medeiros
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Variants ◽  
Complex Traits ◽  
Association Studies ◽  
Cardioembolic Stroke ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Genome Wide Significance

Atrial fibrillation (AF) and stroke are included in a group of complex traits that have been approached regarding of their study by susceptibility genetic determinants. Since 2007, several genome-wide association studies (GWAS) aiming to identify genetic variants modulating AF risk have been conducted. Thus, 11 GWAS have identified 26 SNPs (p < 5 × 10-2), of which 19 reached genome-wide significance (p < 5 × 10-8). From those variants, seven were also associated with cardioembolic stroke and three reached genome-wide significance in stroke GWAS. These associations may shed a light on putative shared etiologic mechanisms between AF and cardioembolic stroke. Additionally, some of these identified variants have been incorporated in genetic risk scores in order to elucidate new approaches of stroke prediction, prevention and treatment.

scholarly journals Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

2019 ◽  
Vol 30 (8) ◽  
pp. 1375-1384 ◽  
Author(s):  
Stephanie Dufek ◽  
Chris Cheshire ◽  
Adam P. Levine ◽  
Richard S. Trompeter ◽  
Naomi Issler ◽  
...  
Keyword(s):  
Immune Response ◽  
Nephrotic Syndrome ◽  
Genetic Identification ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Hla Association ◽  
Genome Wide ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Genome Wide Significance

BackgroundSteroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.MethodsIn an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.ResultsThe GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10−43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10−17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.ConclusionsBecause CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

scholarly journals Association of common genetic variants with brain microbleeds

Neurology ◽  
2020 ◽  
Vol 95 (24) ◽  
pp. e3331-e3343 ◽  
Author(s):  
Maria J. Knol ◽  
Dongwei Lu ◽  
Matthew Traylor ◽  
Hieab H.H. Adams ◽  
José Rafael J. Romero ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Genome Wide Association Studies ◽  
Vessel Disease ◽  
Genome Wide ◽  
Common Genetic Variants

ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe performed genome-wide association studies in 11 population-based cohort studies and 3 case–control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.ResultsBMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21–1.45]; p = 2.5 × 10−10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19–1.50]; p = 1.0 × 10−6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86–1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.ConclusionsGenetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

scholarly journals Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

2019 ◽  
Vol 25 (10) ◽  
pp. 2455-2467 ◽  
Author(s):  
Tim B. Bigdeli ◽  
◽  
Giulio Genovese ◽  
Penelope Georgakopoulos ◽  
Jacquelyn L. Meyers ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Large Fraction ◽  
African Ancestry ◽  
Common Variant ◽  
Human Populations ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Common Genetic Variants

Abstract Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations.

Performance of polygenic risk scores for cancer prediction in an academic biobank.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1528-1528
Author(s):  
Heena Desai ◽  
Anh Le ◽  
Ryan Hausler ◽  
Shefali Verma ◽  
Anurag Verma ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Variants ◽  
Association Studies ◽  
Risk Scores ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
European Americans ◽  
Genome Wide ◽  
Common Genetic Variants

1528 Background: The discovery of rare genetic variants associated with cancer have a tremendous impact on reducing cancer morbidity and mortality when identified; however, rare variants are found in less than 5% of cancer patients. Genome wide association studies (GWAS) have identified hundreds of common genetic variants significantly associated with a number of cancers, but the clinical utility of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear. Methods: We tested the ability of polygenic risk score (PRS) models developed from genome-wide significant variants to differentiate cases versus controls in the Penn Medicine Biobank. Cases for 15 different cancers and cancer-free controls were identified using electronic health record billing codes for 11,524 European American and 5,994 African American individuals from the Penn Medicine Biobank. Results: The discriminatory ability of the 15 PRS models to distinguish their respective cancer cases versus controls ranged from 0.68-0.79 in European Americans and 0.74-0.93 in African Americans. Seven of the 15 cancer PRS trended towards an association with their cancer at a p<0.05 (Table), and PRS for prostate, thyroid and melanoma were significantly associated with their cancers at a bonferroni corrected p<0.003 with OR 1.3-1.6 in European Americans. Conclusions: Our data demonstrate that common variants with significant associations from GWAS studies can distinguish cancer cases versus controls for some cancers in an unselected biobank population. Given the small effects, future studies are needed to determine how best to incorporate PRS with other risk factors in the precision prediction of cancer risk. [Table: see text]

scholarly journals Genome-wide association studies on endometriosis and endometriosis-related infertility

2018 ◽  
Author(s):  
Geneviève Galarneau ◽  
Pierre Fontanillas ◽  
Caterina Clementi ◽  
Tina Hu-Seliger ◽  
David-Emlyn Parfitt ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Reproductive Age ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Model Organisms ◽  
Genome Wide Association Studies ◽  
Gwas Study ◽  
Genome Wide ◽  
Genome Wide Significance

AbstractEndometriosis affects ∼10% of women of reproductive age. It is characterized by the growth of endometrial-like tissue outside the uterus and is frequently associated with severe pain and infertility. We performed the largest endometriosis genome-wide association study (GWAS) to date, with 37,183 cases and 251,258 controls. All women were of European ancestry. We also performed the first GWAS of endometriosis-related infertility, including 2,969 cases and 3,770 controls. Our endometriosis GWAS study replicated, at genome-wide significance, seven loci identified in previous endometriosis GWASs (CELA3A-CDC42, SYNE1, KDR, FSHB-ARL14EP, GREB1, ID4, and CEP112) and identified seven new candidate loci with genome-wide significance (NGF, ATP1B1-F5, CD109, HEY2, OSR2-VPS13B, WT1, and TEX11-SLC7A3). No loci demonstrated genome-wide significance for endometriosis-related infertility, however, the three most strongly associated loci (MCTP1, EPS8L3-CSF1, and LPIN1) were in or near genes associated with female fertility or embryonic lethality in model organisms. These results reveal new candidate genes with potential involvement in the pathophysiology of endometriosis and endometriosis-related infertility.

scholarly journals An integrated platform to systematically identify causal variants and genes for polygenic human traits

2019 ◽  
Author(s):  
Damien J. Downes ◽  
Ron Schwessinger ◽  
Stephanie J. Hill ◽  
Lea Nussbaum ◽  
Caroline Scott ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Association Studies ◽  
Significant Proportion ◽  
Genome Wide Association Studies ◽  
Effector Genes ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Integrated Platform ◽  
Causal Variants

ABSTRACTGenome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is to identify disease-causing variants, the genes they affect, and the cells in which these effects occur. We have developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C and machine learning to address this challenge. Applying this approach to red blood cell traits identifies a significant proportion of known causative variants and their effector genes, which we show can be validated by direct in vivo modelling.

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