Hakon Hakonarson

The Children's Hospital of Philadelphia | CHOP · Center for Applied Genomics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania

Atopic dermatitis (AD) is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to AD genetic association studies are poised to boost power to detect genetic signal and identify ancestry-specific loci contributing to AD risk. Here, we present a multi-ancestry GWAS meta-analysis...

We present a patient with a novel cause of 46,XX ambiguous/androgenous genitalia Differences of Sex Development (DSD). Genome-wide array from blood showed 46,XX with ∼35% mosaic duplication of 76.5 Mb at chromosome 8q13.2-q24.3, containing 257 OMIM genes including ZFPM2 and CYP11B1 . Congenital adrenal hyperplasia testing was negative, testosterone...

Spatially resolved transcriptomics (SRT) technologies have significantly advanced biomedical research, but their data analysis remains challenging due to the discrete nature of the data and the high levels of noise, compounded by complex spatial dependencies. Here, we propose spaVAE, a dependency-aware, deep generative spatial variational autoencod...

The advent of long-read single-cell transcriptome sequencing (lr-scRNA-Seq) represents a significant leap forward in single-cell genomics. With the recent introduction of R10 flowcells by Oxford Nanopore, we propose that previous computational methods designed to handle high sequencing error rates are no longer relevant, and that the prevailing app...

CD8+ T cell dysfunction impedes anti-tumor immunity in solid cancers but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME)...

Voriconazole exposure is associated with skin cancer, but it is unknown how the full spectrum of its metabolizer phenotypes impacts this association. We conducted a retrospective cohort study to determine how variation in metabolism of voriconazole as measured by metabolizer status of CYP2C19 is associated with the total number of skin cancers a pa...

The putative association between serum 25-hydroxyvitamin D concentration [25(OH)D] and the risk of cardioembolic stroke (CES) has been examined in observational studies, which indicate controversial findings. We performed Mendelian randomization (MR) analysis to determine the causal relationship of serum 25(OH)D with the risk of CES. The summary st...

Dyslipidemia, as a metabolic risk factor, with the strongest and most heritable independent cause of cardiovascular diseases worldwide. We investigated the familial transmission patterns of dyslipidemia through a longitudinal family-based cohort, the Tehran Cardiometabolic Genetic Study (TCGS) in Iran. We enrolled 18,729 individuals (45% were males...

Background The genetic architecture of JIA remains only partially comprehended. There is a clear imperative for continued endeavours to uncover insights into the underlying causes of JIA. Methods This study encompassed a comprehensive spectrum of endeavours, including conducting a JIA genome-wide association study (GWAS) meta-analysis that incorpo...

Bronchopulmonary dysplasia (BPD) is a frequent complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of if single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjec...

Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measureme...

Genome-wide association studies (GWAS) have been instrumental in identifying genetic associations for various diseases and traits. However, uncovering genetic underpinnings among traits beyond univariate phenotype associations remains a challenge. Multi-phenotype associations (MPA), or genetic pleiotropy, offer important insights into shared genes...

Objective One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high‐risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. Methods This was a secondary analysis from the SMART study. Patients with high‐risk cfDNA results fo...

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unr...

Introduction: Postural orthostatic tachycardia syndrome (POTS) is more common in Caucasian individuals with a positive family history, while the risk in females is ~4-times of that in males. To date, the etiology of POTS is poorly understood. Hypothesis: Integrative sequencing and translational approaches to identify its genetic underpinning may be...

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity and the dynamics of gene expression, bearing profound significance in stem cell research. Depending on the starting materials used for analysis, scRNA-seq encompasses scRNA-seq and single-nucleus RNA sequencing (snRNA-seq). scRNA-seq excels in capt...

Clostridioides difficile ( C. diff. ) infection (CDI) is a leading cause of hospital acquired diarrhea in North America and Europe and a major cause of morbidity and mortality. Known risk factors do not fully explain CDI susceptibility, and genetic susceptibility is suggested by the fact that some patients with colons that are colonized with C. dif...

Autoimmune diseases arise from atypical immune responses that attack self-tissue epitopes, and their development is intricately connected to the disruption of the JAK-STAT signaling pathway, where SOCS proteins play crucial roles. Conditions such as autoimmune uveitis, psoriasis, lupus, and autoimmune encephalitis exhibit immune system dysfunctions...

Background/Aim: The putative association between serum 25 hydroxyvitamin D concentration 25(OH)D and the risk of cardioembolic stroke (CES) has been examined in observational studies, which indicate controversial findings. We performed Mendelian randomization (MR) analysis to determine the causal relationship of serum 25(OH)D with the risk of CES....

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81...

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 o...

Background/Aim: We performed the Mendelian randomization (MR) analysis to determine the causal relationship of serum monounsaturated fatty acids (MUFAs) with the risk of various cardiovascular diseases (CVDs). Method: The summary statistics dataset related to serum MUFAs was used from the published GWAS of European descent in UK Biobank participa...

Circassians and Chechens in Jordan, both with Caucasian ancestry, are genetically isolated due to high rate of endogamous marriages. Recent interest in these populations has led to studies on their genetic similarities, differences, and epidemiological differences in various diseases. Research has explored their predisposition to conditions like di...

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, k...

Background: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic (P-LP) germline variants in patients without a family history remains unclear. Methods: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer p...

Background/Aim: The possible association between serum monounsaturated fatty acids (MUFAs) and the risk of cardiovascular diseases (CVDs) has been examined in observational studies, which indicate controversial findings. In the current study, we used the Mendelian randomization (MR) analysis to determine the causal relationship of genetically deter...

Owing to the inefficacy of available treatments, the survival rate of patients with metastatic prostate cancer (mPCa) is severely decreased. Therefore, it is crucial to identify new therapeutic targets to increase the survival of mPCa patients. This study aim was to identify the most relevant regulators of mPCa onset by performing two high-throughp...

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide...

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is undefined. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score fo...

We report a 20-year-old, female, adopted Indian patient with over 662 Mb regions of homozy-gosity who presented with intellectual disability, ataxia, schizophrenia, retinal dystrophy, moder-ate-to-severe progressive sensorineural hearing loss (SNHL), congenital hypothyroidism, cleft mi-tral valve with mild mitral valve regurgitation, and dysmorphic...

Background Obesity is a complex trait caused by a combination of genetic, environmental and lifestyle factors that contributes to the risks of numerous serious diseases. Predictive measures of body mass index (BMI) hold significant promise, with implications for the prevention and early intervention of obesity, promoting overall improvement in heal...

Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome seque...

Background: Biliary atresia (BA) is poorly understood and requires liver transplantation (LT) in most children with lifelong risks of immunosuppression. Aims & methods: To determine its genetic basis, we performed GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4654 genetically matched controls. Whole genome seq...

Owing to the inefficacy of available treatments, the survival rate of patients with metastatic prostate cancer (mPCa) is severely decreased. Therefore, it is crucial to identify new therapeutic targets to increase the survival of mPCa patients. This study aim was to identify the most relevant regulators of mPCa onset by performing two high-throughp...

Background: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). Methods: The GIRA model was created to include polygenic risk score calculated from...

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one...

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loc...

Background and aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and associated with risk single nucleotide polymorphism in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, geneti...

Background Ambient air pollution exposure increases the incidence and severity of pediatric asthma. Despite this, we lack effective therapies to protect patients from the impact of ambient air pollution exposure. A roadblock is the inability to identify patients that are affected by air pollution. Objective To examine the association between AAP s...

Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait varian...

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavo...

Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We ass...

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 pa...

A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense varian...

Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Though over 40 genes have been identified as causal...

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impac...

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic devel-opment. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophag...

Purpose: To assess the performance of cell-free DNA (cfDNA) screening to detect sex chromosome aneuploidies (SCA) in an unselected obstetrical population with genetic confirmation. Methods: This was a planned secondary analysis of the multicenter, prospective SMART study. Patients receiving cfDNA results for autosomal aneuploidies and who had co...

Polygenic risk scores (PRS) have potential to improve healthcare by identifying individuals at elevated risk for common complex conditions. Use of PRS in clinical practice, however, requires careful assessment of the needs and capabilities of patients, providers, and healthcare systems. The electronic Medical Records and Genomics (eMERGE) Network i...

Background: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk. Objective: To identify coding genomic variants associated with predisposition to TGCT. Design, setting, and partic...

GATA-binding factor 1 (GATA1) is a transcription factor that governs the development and function of multiple hematopoietic cell lineages. GATA1 is expressed in hematopoietic stem and progenitor cells (HSPCs) and is essential for erythroid lineage commitment; however, whether it plays a role in hematopoietic stem cell (HSC) biology and the developm...

Background Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number...

Objective We sought to develop and evaluate an electronic health record (EHR) genetic testing tracking system to address the barriers and limitations of existing spreadsheet-based workarounds. Materials and Methods We evaluated the spreadsheet-based system using mixed effects logistic regression to identify factors associated with delayed follow u...

The mechanisms by which FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA/TCRVB sequencing to d...

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-anal...

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as domina...

Glioblastoma (GBM) is an aggressive brain cancer with a median survival time of 14.6 months after diagnosis. GBM cells have altered metabolism and exhibit the Warburg effect, preferentially producing lactate under aerobic conditions. After standard-of-care treatment for GBM, there is an almost 100% recurrence rate. Hypoxia-adapted, treatment-resist...

Hallux valgus is a common form of foot deformity, and genetic factors contribute substantially to the pathogenesis of hallux valgus deformity. We conducted a genetic study on the structural variants underlying familial hallux valgus using whole exome sequencing approach. Twenty individuals from five hallux valgus families and two sporadic cases wer...

BAG3 is a 575 amino acid protein that is found throughout the animal kingdom and homologs have been identified in plants. The protein is expressed ubiquitously but is most prominent in cardiac muscle, skeletal muscle, the brain and in many cancers. We describe BAG3 as a quintessential multi-functional protein. It supports autophagy of both misfolde...

The inflammatory bowel diseases, Crohn disease and ulcerative colitis, are caused by the immune system’s dysregulated response to gut flora and environmental exposures in genetically susceptible individuals. The last 20 years have shown great progress in understanding the basis of this genetic susceptibility. The first efforts involved epidemiology...

Background Cardiometabolic diseases are highly comorbid, but their relationship with female‐specific or overwhelmingly female‐predominant health conditions (breast cancer, endometriosis, pregnancy complications) is understudied. This study aimed to estimate the cross‐trait genetic overlap and influence of genetic burden of cardiometabolic traits on...

With the advances in single-cell sequencing techniques, numerous analytical methods have been developed for delineating cell development. However, most are based on Euclidean space, which would distort the complex hierarchical structure of cell differentiation. Recently, methods acting on hyperbolic space have been proposed to visualize hierarchica...

We report a 20-year-old female, adopted Indian patient with over 662 Mb regions of homozygosity who presented with variants associated with symptoms in BBS6, STRC, and DUOX2 genes. And a VUS in the TNNT2 gene, so far without clinical correlation. Symptoms are not explained by only one gene.

Introduction Type 1 diabetes, a disorder caused by autoimmune destruction of pancreatic insulin-producing cells, is more difficult to manage when it presents at a younger age. We sought to identify genetic correlates of the age of onset by conducting the first genome-wide association study (GWAS) treating the age of first diagnosis as a quantitativ...

AMOTL1 encodes angiomotin‐like protein 1, an actin‐binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricula...

Objective We sought to develop and evaluate an electronic health record (EHR) genetic testing tracking system to address the barriers and limitations of existing spreadsheet-based workarounds. Materials and Methods We evaluated the spreadsheet-based system using mixed effects logistic regression to identify factors associated with delayed follow up...

Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear. Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma p...

LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes), encoded by the TNFSF14 gene, is a cytokine belonging to the TNF superfamily. On binding to its receptors, herpes virus entry mediator and lymphotoxin β receptor, it activates...

Background and Objectives The term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the ANO10 gene. Little is known about the molecular role...

Thoracic insufficiency syndromes are a genetically and phenotypically heterogeneous group of disorders characterized by congenital abnormalities or progressive deformation of the chest wall and/or vertebrae that result in restrictive lung disease and compromised respiratory capacity. We performed whole exome sequencing on a cohort of 42 children wi...

Background While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavore...

The cover image is based on the Clinical Report A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro‐Caribbean individual by Mary Maj et al., https://doi.org/10.1002/mgg3.2064 Image Credit: Used with permission, Sarah Gluschitz, St. George’s University, Department of Anatomical Sciences

Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies. Although varicose veins are heritable and epidemiologic studies have identified several candidate varicose vein risk factors, the molecular and genetic basis remains uncertain. Here we analyzed the contribution of common genetic variants t...

Purpose: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk....

Background: Peripheral blood mononuclear cells (PBMCs) are widely used as a model in the study of different human diseases. There is often a time delay from blood collection to PBMC isolation during the sampling process, which can result in an experimental bias, particularly when performing single cell RNA-seq (scRNAseq) studies. Methods: This s...

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

[This corrects the article DOI: 10.1016/j.xhgg.2022.100102.].

Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understa...

Interruption of the aortic arch (IAA) is a rare but life-threatening congenital heart defect if not corrected in the neonatal period. IAA type B is highly correlated with 22q11.2 deletion syndrome (22q11.2DS); approximately 50% of patients with IAA type B also have 22q11.2DS (Peyvandi et al., 2013; Goldmuntz et al. 1998). Early identification and r...