This page has only limited features, please log in for full access.

Unclaimed
Hakon Hakonarson
The Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, USA

Honors and Awards

The user has no records in this section


Career Timeline

The user has no records in this section.


Short Biography

The user biography is not available.
Following
Followers
Co Authors
The list of users this user is following is empty.
Following: 0 users

Feed

Journal article
Published: 06 August 2021 in Scientific Reports
Reads 0
Downloads 0

With polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included. The first cohort consisted of 3302 T1D cases and 6181 controls, and the independent second cohort consisted of 3297 T1D cases and 6169 controls. Cases with low T1D PRS were identified using PRSice-2 and compared to controls with low T1D PRS by genome-wide association (GWA) test. Thirteen novel genetic loci with high imputation quality (Quality Score r2 > 0.91) were identified of SNPs/SNVs associated with low PRS T1D at genome-wide significance (P ≤ 5.0 × E−08), in addition to 4 established T1D loci, 3 reported loci by our previous study, as well as 9 potential novel loci represented by rare SNVs, but with relatively low imputation quality (Quality Score r2 < 0.90). For the 13 novel loci, 9 regions have been reported of association with obesity related traits by previous GWA studies. Three loci encoding long intergenic non-protein coding RNAs (lncRNA), and 2 loci involved in N-linked glycosylation are also highlighted in this study.

ACS Style

Jingchun Qu; Hui-Qi Qu; Jonathan P. Bradfield; Joseph T. Glessner; Xiao Chang; Lifeng Tian; Michael March; John J. Connolly; Jeffrey D. Roizen; Patrick M. A. Sleiman; Hakon Hakonarson. Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients. Scientific Reports 2021, 11, 1 .

AMA Style

Jingchun Qu, Hui-Qi Qu, Jonathan P. Bradfield, Joseph T. Glessner, Xiao Chang, Lifeng Tian, Michael March, John J. Connolly, Jeffrey D. Roizen, Patrick M. A. Sleiman, Hakon Hakonarson. Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients. Scientific Reports. 2021; 11 ():1.

Chicago/Turabian Style

Jingchun Qu; Hui-Qi Qu; Jonathan P. Bradfield; Joseph T. Glessner; Xiao Chang; Lifeng Tian; Michael March; John J. Connolly; Jeffrey D. Roizen; Patrick M. A. Sleiman; Hakon Hakonarson. 2021. "Insights into non-autoimmune type 1 diabetes with 13 novel loci in low polygenic risk score patients." Scientific Reports 11, no. : 1.

Article
Published: 23 July 2021 in Communications Biology
Reads 0
Downloads 0

Type 1 diabetes (T1D) patients with low genetic risk scores (GRS) may be non-autoimmune or autoimmune mediated by other genetic loci. The T1D-GRS2 provides us an opportunity to look into the genetic architecture of these patients. A total of 18,949 European individuals were included in this study, including 6599 T1D cases and 12,323 controls. 957 (14.5%) T1D patients were identified with low GRS (GRS < 8.43). The genome-wide association study on these patients identified 41 unreported loci. Two loci with common variants and 39 loci with rare variants were identified in this study. This study identified common SNPs associated with both low GRS T1D and expression levels of the interferon-α-induced MNDA gene, indicating the role of viral infection in T1D. Interestingly, 16 of the 41 unreported loci have been linked to autism spectrum disorder (ASD) by previous studies, suggesting that genes residing at these loci may underlie both T1D and autism.

ACS Style

Hui-Qi Qu; Jingchun Qu; Jonathan Bradfield; Luc Marchand; Joseph Glessner; Xiao Chang; Michael March; Jin Li; John J. Connolly; Jeffrey D. Roizen; Patrick Sleiman; Constantin Polychronakos; Hakon Hakonarson. Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci. Communications Biology 2021, 4, 1 -10.

AMA Style

Hui-Qi Qu, Jingchun Qu, Jonathan Bradfield, Luc Marchand, Joseph Glessner, Xiao Chang, Michael March, Jin Li, John J. Connolly, Jeffrey D. Roizen, Patrick Sleiman, Constantin Polychronakos, Hakon Hakonarson. Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci. Communications Biology. 2021; 4 (1):1-10.

Chicago/Turabian Style

Hui-Qi Qu; Jingchun Qu; Jonathan Bradfield; Luc Marchand; Joseph Glessner; Xiao Chang; Michael March; Jin Li; John J. Connolly; Jeffrey D. Roizen; Patrick Sleiman; Constantin Polychronakos; Hakon Hakonarson. 2021. "Genetic architecture of type 1 diabetes with low genetic risk score informed by 41 unreported loci." Communications Biology 4, no. 1: 1-10.

Article
Published: 22 July 2021
Reads 0
Downloads 0

LIGHT, encoded by the TNFSF14 gene, is a cytokine belonging to the tumor necrosis factor superfamily. Upon binding to its receptors, HVEM and LTBR, it activates inflammatory responses. We used a single-molecule immunoassay to determine the circulating levels of free LIGHT in plasma from pediatric patients with Crohn’s disease (N = 183) and a panel of healthy pediatric reference samples (N = 9). LIGHT levels were greatly elevated in Crohn’s disease (average of 305 pg/ml versus 57 pg/ml in controls, P < 0.0001). We performed correlational analyses between LIGHT levels and the clinical characteristics of the Crohn’s cohort, including age, Montreal classification, family history, medical/surgical therapy, and routine blood test parameters. We found statistically significant correlation between white blood cell count and free LIGHT (P < 0.046). Our results support the hypothesis that elevated levels of the cytokine contribute to the pathology of Crohn’s disease and that therapies to neutralize free LIGHT with antibodies may be beneficial.

ACS Style

Christopher J. Cardinale; Debra J. Abrams; Frank D. Mentch; John A. Cardinale; Charlly Kao; Patrick M.A. Sleiman; Hakon Hakonarson. Elevated levels of the cytokine LIGHT in Crohn’s disease. 2021, 1 .

AMA Style

Christopher J. Cardinale, Debra J. Abrams, Frank D. Mentch, John A. Cardinale, Charlly Kao, Patrick M.A. Sleiman, Hakon Hakonarson. Elevated levels of the cytokine LIGHT in Crohn’s disease. . 2021; ():1.

Chicago/Turabian Style

Christopher J. Cardinale; Debra J. Abrams; Frank D. Mentch; John A. Cardinale; Charlly Kao; Patrick M.A. Sleiman; Hakon Hakonarson. 2021. "Elevated levels of the cytokine LIGHT in Crohn’s disease." , no. : 1.

Journal article
Published: 01 July 2021 in Genes
Reads 0
Downloads 0

Conotruncal defects with normally related great vessels (CTD-NRGVs) occur in both patients with and without 22q11.2 deletion syndrome (22q11.2DS), but it is unclear to what extent the genetically complex etiologies of these heart defects may overlap across these two groups, potentially involving variation within and/or outside of the 22q11.2 region. To explore this potential overlap, we conducted genome-wide SNP-level, gene-level, and gene set analyses using common variants, separately in each of five cohorts, including two with 22q11.2DS (N = 1472 total cases) and three without 22q11.2DS (N = 935 total cases). Results from the SNP-level analyses were combined in meta-analyses, and summary statistics from these analyses were also used in gene and gene set analyses. Across all these analyses, no association was significant after correction for multiple comparisons. However, several SNPs, genes, and gene sets with suggestive evidence of association were identified. For common inherited variants, we did not identify strong evidence for shared genomic mechanisms for CTD-NRGVs across individuals with and without 22q11.2 deletions. Nevertheless, several of our top gene-level and gene set results have been linked to cardiogenesis and may represent candidates for future work.

ACS Style

Omobola Oluwafemi; Fadi Musfee; Laura Mitchell; Elizabeth Goldmuntz; Hongbo Xie; Hakon Hakonarson; Bernice Morrow; Tingwei Guo; Deanne Taylor; Donna McDonald-McGinn; Beverly Emanuel; A. Agopian. Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States. Genes 2021, 12, 1030 .

AMA Style

Omobola Oluwafemi, Fadi Musfee, Laura Mitchell, Elizabeth Goldmuntz, Hongbo Xie, Hakon Hakonarson, Bernice Morrow, Tingwei Guo, Deanne Taylor, Donna McDonald-McGinn, Beverly Emanuel, A. Agopian. Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States. Genes. 2021; 12 (7):1030.

Chicago/Turabian Style

Omobola Oluwafemi; Fadi Musfee; Laura Mitchell; Elizabeth Goldmuntz; Hongbo Xie; Hakon Hakonarson; Bernice Morrow; Tingwei Guo; Deanne Taylor; Donna McDonald-McGinn; Beverly Emanuel; A. Agopian. 2021. "Genome-Wide Association Studies of Conotruncal Heart Defects with Normally Related Great Vessels in the United States." Genes 12, no. 7: 1030.

Journal article
Published: 17 June 2021 in Nature Genetics
Reads 0
Downloads 0

Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome. These include discordant pleiotropy in the HLA region between lipids and multiple sclerosis and putative causal paths between triglycerides and gout, among several others. Our findings give insights into the genetic basis of the relationship between plasma lipids and diseases on a phenome-wide scale and can provide context for future prevention and treatment strategies. An analytical framework based on transcriptome-wide association and electronic medical records provides insights into the relationship between plasma lipids and complex diseases on a phenome-wide scale.

ACS Style

Yogasudha Veturi; Anastasia Lucas; Yuki Bradford; Daniel Hui; Scott Dudek; Elizabeth Theusch; Anurag Verma; Jason E. Miller; Iftikhar Kullo; Hakon Hakonarson; Patrick Sleiman; Daniel Schaid; Charles M. Stein; Digna R. Velez Edwards; Qiping Feng; Wei-Qi Wei; Marisa W. Medina; Ronald M. Krauss; Thomas J. Hoffmann; Neil Risch; Benjamin F. Voight; Daniel J. Rader; Marylyn D. Ritchie. A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts. Nature Genetics 2021, 1 -10.

AMA Style

Yogasudha Veturi, Anastasia Lucas, Yuki Bradford, Daniel Hui, Scott Dudek, Elizabeth Theusch, Anurag Verma, Jason E. Miller, Iftikhar Kullo, Hakon Hakonarson, Patrick Sleiman, Daniel Schaid, Charles M. Stein, Digna R. Velez Edwards, Qiping Feng, Wei-Qi Wei, Marisa W. Medina, Ronald M. Krauss, Thomas J. Hoffmann, Neil Risch, Benjamin F. Voight, Daniel J. Rader, Marylyn D. Ritchie. A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts. Nature Genetics. 2021; ():1-10.

Chicago/Turabian Style

Yogasudha Veturi; Anastasia Lucas; Yuki Bradford; Daniel Hui; Scott Dudek; Elizabeth Theusch; Anurag Verma; Jason E. Miller; Iftikhar Kullo; Hakon Hakonarson; Patrick Sleiman; Daniel Schaid; Charles M. Stein; Digna R. Velez Edwards; Qiping Feng; Wei-Qi Wei; Marisa W. Medina; Ronald M. Krauss; Thomas J. Hoffmann; Neil Risch; Benjamin F. Voight; Daniel J. Rader; Marylyn D. Ritchie. 2021. "A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts." Nature Genetics , no. : 1-10.

Journal article
Published: 15 June 2021 in American Journal of Medical Genetics Part A
Reads 0
Downloads 0

Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.

ACS Style

Alanna Strong; Laurie Simone; Anthony Krentz; Courtney Vaccaro; Deborah Watson; Hayley Ron; Jennifer M. Kalish; Helio F. Pedro; Elaine H. Zackai; Hakon Hakonarson. Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes. American Journal of Medical Genetics Part A 2021, 185, 2409 -2416.

AMA Style

Alanna Strong, Laurie Simone, Anthony Krentz, Courtney Vaccaro, Deborah Watson, Hayley Ron, Jennifer M. Kalish, Helio F. Pedro, Elaine H. Zackai, Hakon Hakonarson. Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes. American Journal of Medical Genetics Part A. 2021; 185 (8):2409-2416.

Chicago/Turabian Style

Alanna Strong; Laurie Simone; Anthony Krentz; Courtney Vaccaro; Deborah Watson; Hayley Ron; Jennifer M. Kalish; Helio F. Pedro; Elaine H. Zackai; Hakon Hakonarson. 2021. "Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes." American Journal of Medical Genetics Part A 185, no. 8: 2409-2416.

Genetics
Published: 04 June 2021 in PLOS Genetics
Reads 0
Downloads 0

Assumptions are made about the genetic model of single nucleotide polymorphisms (SNPs) when choosing a traditional genetic encoding: additive, dominant, and recessive. Furthermore, SNPs across the genome are unlikely to demonstrate identical genetic models. However, running SNP-SNP interaction analyses with every combination of encodings raises the multiple testing burden. Here, we present a novel and flexible encoding for genetic interactions, the elastic data-driven genetic encoding (EDGE), in which SNPs are assigned a heterozygous value based on the genetic model they demonstrate in a dataset prior to interaction testing. We assessed the power of EDGE to detect genetic interactions using 29 combinations of simulated genetic models and found it outperformed the traditional encoding methods across 10%, 30%, and 50% minor allele frequencies (MAFs). Further, EDGE maintained a low false-positive rate, while additive and dominant encodings demonstrated inflation. We evaluated EDGE and the traditional encodings with genetic data from the Electronic Medical Records and Genomics (eMERGE) Network for five phenotypes: age-related macular degeneration (AMD), age-related cataract, glaucoma, type 2 diabetes (T2D), and resistant hypertension. A multi-encoding genome-wide association study (GWAS) for each phenotype was performed using the traditional encodings, and the top results of the multi-encoding GWAS were considered for SNP-SNP interaction using the traditional encodings and EDGE. EDGE identified a novel SNP-SNP interaction for age-related cataract that no other method identified: rs7787286 (MAF: 0.041; intergenic region of chromosome 7)–rs4695885 (MAF: 0.34; intergenic region of chromosome 4) with a Bonferroni LRT p of 0.018. A SNP-SNP interaction was found in data from the UK Biobank within 25 kb of these SNPs using the recessive encoding: rs60374751 (MAF: 0.030) and rs6843594 (MAF: 0.34) (Bonferroni LRT p: 0.026). We recommend using EDGE to flexibly detect interactions between SNPs exhibiting diverse action.

ACS Style

Molly A. Hall; John Wallace; Anastasia M. Lucas; Yuki Bradford; Shefali S. Verma; Bertram Müller-Myhsok; Kristin Passero; Jiayan Zhou; John McGuigan; Beibei Jiang; Sarah A. Pendergrass; Yanfei Zhang; Peggy Peissig; Murray Brilliant; Patrick Sleiman; Hakon Hakonarson; John B. Harley; Krzysztof Kiryluk; Kristel Van Steen; Jason H. Moore; Marylyn D. Ritchie. Novel EDGE encoding method enhances ability to identify genetic interactions. PLOS Genetics 2021, 17, e1009534 .

AMA Style

Molly A. Hall, John Wallace, Anastasia M. Lucas, Yuki Bradford, Shefali S. Verma, Bertram Müller-Myhsok, Kristin Passero, Jiayan Zhou, John McGuigan, Beibei Jiang, Sarah A. Pendergrass, Yanfei Zhang, Peggy Peissig, Murray Brilliant, Patrick Sleiman, Hakon Hakonarson, John B. Harley, Krzysztof Kiryluk, Kristel Van Steen, Jason H. Moore, Marylyn D. Ritchie. Novel EDGE encoding method enhances ability to identify genetic interactions. PLOS Genetics. 2021; 17 (6):e1009534.

Chicago/Turabian Style

Molly A. Hall; John Wallace; Anastasia M. Lucas; Yuki Bradford; Shefali S. Verma; Bertram Müller-Myhsok; Kristin Passero; Jiayan Zhou; John McGuigan; Beibei Jiang; Sarah A. Pendergrass; Yanfei Zhang; Peggy Peissig; Murray Brilliant; Patrick Sleiman; Hakon Hakonarson; John B. Harley; Krzysztof Kiryluk; Kristel Van Steen; Jason H. Moore; Marylyn D. Ritchie. 2021. "Novel EDGE encoding method enhances ability to identify genetic interactions." PLOS Genetics 17, no. 6: e1009534.

Preprint content
Published: 27 May 2021 in medRxiv
Reads 0
Downloads 0

Objective The cytokines, LIGHT (TNFSF14) and Interleukin-18 (IL-18), are two important therapeutic targets due to their central roles in the function of activated T cells and inflammatory injury. LIGHT was recently shown to play a major role in COVID19 induced acute respiratory distress syndrome (ARDS), reducing mortality and hospital stay. This study aims to investigate the associations of LIGHT and IL-18 with non-COVID19 related ARDS, acute hypoxic respiratory failure (AHRF) or acute kidney injury (AKI), secondary to viral or bacterial sepsis. Research Design and Methods A cohort of 280 subjects diagnosed with sepsis, including 91 cases with sepsis triggered by viral infections, were investigated in this study and compared to healthy controls. Serum LIGHT, IL-18, and 59 other biomarkers (cytokines, chemokines and acute-phase reactants) were measured and associated with symptom severity. Results ARDS was observed in 36% of the patients, with 29% of the total patient cohort developing multi-organ failure (failure of two or more organs). We observed significantly increased LIGHT level (>2SD above mean of healthy subjects) in both bacterial sepsis patients (P=1.80E-05) and patients with sepsis from viral infections (P=1.78E-03). In bacterial sepsis, increased LIGHT level associated with ARDS, AKI and higher Apache III scores, findings also supported by correlations of LIGHT with other biomarkers of organ failures, suggesting LIGHT may be an inflammatory driver. IL-18 levels were highly variable across individuals, and consistently correlated with Apache III scores, mortality, and AKI, in both bacterial and viral sepsis. Conclusions For the first time, we demonstrate independent effects of LIGHT and IL-18 in septic organ failures. LIGHT levels are significantly elevated in non-COVID19 sepsis patients with ARDS and/or multi-organ failures suggesting that anti-LIGHT therapy may be effective therapy in a subset of patients with sepsis. Given the large variance of plasma IL-18 among septic subjects, targeting this pathway raises opportunities that require a precision application.

ACS Style

Hui-Qi Qu; Jingchun Qu; Thomas Dunn; James Snyder; Todd A. Miano; John Connolly; Joseph Glessner; Brian J. Anderson; John P. Reilly; Tiffanie K. Jones; Heather M. Giannini; Roseline S. Agyekum; Ariel R. Weisman; Caroline A.G. Ittner; Laura G. Rodrigues; Charlly Kao; Michael G.S. Shashaty; Patrick Sleiman; Nuala J. Meyer; Hakon Hakonarson. Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries. medRxiv 2021, 1 .

AMA Style

Hui-Qi Qu, Jingchun Qu, Thomas Dunn, James Snyder, Todd A. Miano, John Connolly, Joseph Glessner, Brian J. Anderson, John P. Reilly, Tiffanie K. Jones, Heather M. Giannini, Roseline S. Agyekum, Ariel R. Weisman, Caroline A.G. Ittner, Laura G. Rodrigues, Charlly Kao, Michael G.S. Shashaty, Patrick Sleiman, Nuala J. Meyer, Hakon Hakonarson. Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries. medRxiv. 2021; ():1.

Chicago/Turabian Style

Hui-Qi Qu; Jingchun Qu; Thomas Dunn; James Snyder; Todd A. Miano; John Connolly; Joseph Glessner; Brian J. Anderson; John P. Reilly; Tiffanie K. Jones; Heather M. Giannini; Roseline S. Agyekum; Ariel R. Weisman; Caroline A.G. Ittner; Laura G. Rodrigues; Charlly Kao; Michael G.S. Shashaty; Patrick Sleiman; Nuala J. Meyer; Hakon Hakonarson. 2021. "Elevation of Circulating LIGHT (TNFSF14) and Interleukin-18 Levels in Sepsis-Induced Multi-Organ Injuries." medRxiv , no. : 1.

Journal article
Published: 22 May 2021 in Human Reproduction
Reads 0
Downloads 0

STUDY QUESTION Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? SUMMARY ANSWER By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. WHAT IS KNOWN ALREADY AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. STUDY DESIGN, SIZE, DURATION We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. PARTICIPANTS/MATERIALS, SETTING, METHODS Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. MAIN RESULTS AND THE ROLE OF CHANCE We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10−7. We detected one new association (10p15) at P < 5 × 10−8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. WIDER IMPLICATIONS OF THE FINDINGS Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

ACS Style

C Sarnowski; D L Cousminer; N Franceschini; L M Raffield; G Jia; L Fernández-Rhodes; S F A Grant; H Hakonarson; L A Lange; J Long; T Sofer; R Tao; R B Wallace; Q Wong; G Zirpoli; E Boerwinkle; J P Bradfield; A Correa; C L Kooperberg; K E North; J R Palmer; B S Zemel; W Zheng; J M Murabito; K L Lunetta. Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche. Human Reproduction 2021, 36, 1999 -2010.

AMA Style

C Sarnowski, D L Cousminer, N Franceschini, L M Raffield, G Jia, L Fernández-Rhodes, S F A Grant, H Hakonarson, L A Lange, J Long, T Sofer, R Tao, R B Wallace, Q Wong, G Zirpoli, E Boerwinkle, J P Bradfield, A Correa, C L Kooperberg, K E North, J R Palmer, B S Zemel, W Zheng, J M Murabito, K L Lunetta. Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche. Human Reproduction. 2021; 36 (7):1999-2010.

Chicago/Turabian Style

C Sarnowski; D L Cousminer; N Franceschini; L M Raffield; G Jia; L Fernández-Rhodes; S F A Grant; H Hakonarson; L A Lange; J Long; T Sofer; R Tao; R B Wallace; Q Wong; G Zirpoli; E Boerwinkle; J P Bradfield; A Correa; C L Kooperberg; K E North; J R Palmer; B S Zemel; W Zheng; J M Murabito; K L Lunetta. 2021. "Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche." Human Reproduction 36, no. 7: 1999-2010.

Journal article
Published: 13 May 2021 in Blood
Reads 0
Downloads 0

Patients with familial platelet disorder with a predisposition to myeloid malignancy (FPDMM) harbor germline monoallelic mutations in a key hematopoietic transcription factor, RUNX-1. Previous studies of FPDMM have focused on megakaryocyte (Mk) differentiation and platelet production and signaling. However, the effects of RUNX-1 haploinsufficiency on hematopoietic progenitor cells (HPCs) and subsequent megakaryopoiesis remains incomplete. We studied induced pluripotent stem cell (iPSC)–derived HPCs (iHPCs) and Mks (iMks) from both patient-derived lines and a wild-type (WT) line modified to be RUNX-1 haploinsufficient (RUNX-1+/−), each compared with their isogenic WT control. All RUNX-1+/− lines showed decreased iMk yield and depletion of an Mk-biased iHPC subpopulation. To investigate global and local gene expression changes underlying this iHPC shift, single-cell RNA sequencing was performed on sorted FPDMM and control iHPCs. We defined several cell subpopulations in the Mk-biased iHPCs. Analyses of gene sets upregulated in FPDMM iHPCs indicated enrichment for response to stress, regulation of signal transduction, and immune signaling-related gene sets. Immunoblot analyses in FPDMM iMks were consistent with these findings, but also identified augmented baseline c-Jun N-terminal kinase (JNK) phosphorylation, known to be activated by transforming growth factor-β1 (TGF-β1) and cellular stressors. These findings were confirmed in adult human CD34+-derived stem and progenitor cells (HSPCs) transduced with lentiviral RUNX1 short hairpin RNA to mimic RUNX-1+/−. In both iHPCs and CD34+-derived HSPCs, targeted inhibitors of JNK and TGF-β1 pathways corrected the megakaryopoietic defect. We propose that such intervention may correct the thrombocytopenia in patients with FPDMM.

ACS Style

Brian Estevez; Sara Borst; Danuta Jadwiga Jarocha; Varun S Sudunagunta; Michael Gonzalez; James Garifallou; Hakon Hakonarson; Peng Gao; Kai Tan; Paul P Liu; Sumedha Bagga; Nicholas Holdreith; Wei Tong; Nancy A Speck; Deborah L. French; Paul Gadue; Mortimer Poncz. RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells. Blood 2021, 137, 2662 -2675.

AMA Style

Brian Estevez, Sara Borst, Danuta Jadwiga Jarocha, Varun S Sudunagunta, Michael Gonzalez, James Garifallou, Hakon Hakonarson, Peng Gao, Kai Tan, Paul P Liu, Sumedha Bagga, Nicholas Holdreith, Wei Tong, Nancy A Speck, Deborah L. French, Paul Gadue, Mortimer Poncz. RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells. Blood. 2021; 137 (19):2662-2675.

Chicago/Turabian Style

Brian Estevez; Sara Borst; Danuta Jadwiga Jarocha; Varun S Sudunagunta; Michael Gonzalez; James Garifallou; Hakon Hakonarson; Peng Gao; Kai Tan; Paul P Liu; Sumedha Bagga; Nicholas Holdreith; Wei Tong; Nancy A Speck; Deborah L. French; Paul Gadue; Mortimer Poncz. 2021. "RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells." Blood 137, no. 19: 2662-2675.

Research article
Published: 12 May 2021 in Science Advances
Reads 0
Downloads 0

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50% of the patients remains elusive. We describe pathogenic variants in SMARCA5, encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 Drosophila ortholog Iswi led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

ACS Style

Dong Li; Qin Wang; Naihua N. Gong; Alina Kurolap; Hagit Baris Feldman; Nikolas Boy; Melanie Brugger; Katheryn Grand; Kirsty McWalter; Maria J. Guillen Sacoto; Emma Wakeling; Jane Hurst; Michael E. March; Elizabeth J. Bhoj; Małgorzata J. M. Nowaczyk; Claudia Gonzaga-Jauregui; Mariam Mathew; Ashita Dava-Wala; Amy Siemon; Dennis Bartholomew; Yue Huang; Hane Lee; Julian A. Martinez-Agosto; Eva M. C. Schwaibold; Theresa Brunet; Daniela Choukair; Lynn S. Pais; Susan M. White; John Christodoulou; Dana Brown; Kristin Lindstrom; Theresa Grebe; Dov Tiosano; Matthew S. Kayser; Tiong Yang Tan; Matthew A. Deardorff; Yuanquan Song; Hakon Hakonarson. Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features. Science Advances 2021, 7, eabf2066 .

AMA Style

Dong Li, Qin Wang, Naihua N. Gong, Alina Kurolap, Hagit Baris Feldman, Nikolas Boy, Melanie Brugger, Katheryn Grand, Kirsty McWalter, Maria J. Guillen Sacoto, Emma Wakeling, Jane Hurst, Michael E. March, Elizabeth J. Bhoj, Małgorzata J. M. Nowaczyk, Claudia Gonzaga-Jauregui, Mariam Mathew, Ashita Dava-Wala, Amy Siemon, Dennis Bartholomew, Yue Huang, Hane Lee, Julian A. Martinez-Agosto, Eva M. C. Schwaibold, Theresa Brunet, Daniela Choukair, Lynn S. Pais, Susan M. White, John Christodoulou, Dana Brown, Kristin Lindstrom, Theresa Grebe, Dov Tiosano, Matthew S. Kayser, Tiong Yang Tan, Matthew A. Deardorff, Yuanquan Song, Hakon Hakonarson. Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features. Science Advances. 2021; 7 (20):eabf2066.

Chicago/Turabian Style

Dong Li; Qin Wang; Naihua N. Gong; Alina Kurolap; Hagit Baris Feldman; Nikolas Boy; Melanie Brugger; Katheryn Grand; Kirsty McWalter; Maria J. Guillen Sacoto; Emma Wakeling; Jane Hurst; Michael E. March; Elizabeth J. Bhoj; Małgorzata J. M. Nowaczyk; Claudia Gonzaga-Jauregui; Mariam Mathew; Ashita Dava-Wala; Amy Siemon; Dennis Bartholomew; Yue Huang; Hane Lee; Julian A. Martinez-Agosto; Eva M. C. Schwaibold; Theresa Brunet; Daniela Choukair; Lynn S. Pais; Susan M. White; John Christodoulou; Dana Brown; Kristin Lindstrom; Theresa Grebe; Dov Tiosano; Matthew S. Kayser; Tiong Yang Tan; Matthew A. Deardorff; Yuanquan Song; Hakon Hakonarson. 2021. "Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features." Science Advances 7, no. 20: eabf2066.

Clinical report
Published: 07 May 2021 in American Journal of Medical Genetics Part A
Reads 0
Downloads 0

Ring‐finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi‐organ RNF213‐spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C‐terminal RNF213 missense variants.

ACS Style

Alanna Strong; Gina O'Grady; Evelyn Shih; Jonathan R. Bishop; Kathleen Loomes; Tamir Diamond; Erum A. Hartung; William Wong; Sanmati Cuddapah; Anne Marie Cahill; Cuiping Hou; Diana Slater; Courtney Vaccaro; Deborah Watson; Dong Li; Hakon Hakonarson. A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213. American Journal of Medical Genetics Part A 2021, 185, 2168 -2174.

AMA Style

Alanna Strong, Gina O'Grady, Evelyn Shih, Jonathan R. Bishop, Kathleen Loomes, Tamir Diamond, Erum A. Hartung, William Wong, Sanmati Cuddapah, Anne Marie Cahill, Cuiping Hou, Diana Slater, Courtney Vaccaro, Deborah Watson, Dong Li, Hakon Hakonarson. A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213. American Journal of Medical Genetics Part A. 2021; 185 (7):2168-2174.

Chicago/Turabian Style

Alanna Strong; Gina O'Grady; Evelyn Shih; Jonathan R. Bishop; Kathleen Loomes; Tamir Diamond; Erum A. Hartung; William Wong; Sanmati Cuddapah; Anne Marie Cahill; Cuiping Hou; Diana Slater; Courtney Vaccaro; Deborah Watson; Dong Li; Hakon Hakonarson. 2021. "A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213." American Journal of Medical Genetics Part A 185, no. 7: 2168-2174.

Research letter
Published: 07 May 2021 in FEBS Letters
Reads 0
Downloads 0

We previously observed enhanced immunoglobulin A (IgA) responses in severe COVID‐19, which might confer damaging effects. Given the important role of IgA in immune and inflammatory responses, the aim of this study was to investigate the dynamic response of the IgA isotype switch factor TGF‐β1 in COVID‐19 patients. We observed, in a total of 153 COVID‐19 patients, that the serum levels of TGF‐β1 were increased significantly at the early and middle stages of COVID‐19, and correlated with the levels of SARS‐CoV‐2‐specific IgA, as well as with the APACHE‐II score in patients with severe disease. In view of the genetic association of the TGF‐β1 activator THBS3 with severe COVID‐19 identified by the COVID‐19 Host Genetics Initiative, this study suggests TGF‐β1 may play a key role in COVID‐19.

ACS Style

Er‐Yi Wang; Hao Chen; Bao‐Qing Sun; Hui Wang; Hui‐Qi Qu; Yichuan Liu; Xi‐Zhuo Sun; Jingchun Qu; Zhang‐Fu Fang; Lifeng Tian; Yi‐Feng Zeng; Shau‐Ku Huang; Hakon Hakonarson; Zhi‐Gang Liu. Serum levels of the IgA isotype switch factor TGF‐β1 are elevated in patients with COVID‐19. FEBS Letters 2021, 1 .

AMA Style

Er‐Yi Wang, Hao Chen, Bao‐Qing Sun, Hui Wang, Hui‐Qi Qu, Yichuan Liu, Xi‐Zhuo Sun, Jingchun Qu, Zhang‐Fu Fang, Lifeng Tian, Yi‐Feng Zeng, Shau‐Ku Huang, Hakon Hakonarson, Zhi‐Gang Liu. Serum levels of the IgA isotype switch factor TGF‐β1 are elevated in patients with COVID‐19. FEBS Letters. 2021; ():1.

Chicago/Turabian Style

Er‐Yi Wang; Hao Chen; Bao‐Qing Sun; Hui Wang; Hui‐Qi Qu; Yichuan Liu; Xi‐Zhuo Sun; Jingchun Qu; Zhang‐Fu Fang; Lifeng Tian; Yi‐Feng Zeng; Shau‐Ku Huang; Hakon Hakonarson; Zhi‐Gang Liu. 2021. "Serum levels of the IgA isotype switch factor TGF‐β1 are elevated in patients with COVID‐19." FEBS Letters , no. : 1.

Journal article
Published: 05 May 2021 in Journal of Experimental Medicine
Reads 0
Downloads 0

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro–B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro– to pre–B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1’s critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

ACS Style

Carole Le Coz; David N. Nguyen; Chun Su; Brian E. Nolan; Amanda V. Albrecht; Suela Xhani; Di Sun; Benjamin Demaree; Piyush Pillarisetti; Caroline Khanna; Francis Wright; Peixin Amy Chen; Samuel Yoon; Amy L. Stiegler; Kelly Maurer; James P. Garifallou; Amy Rymaszewski; Steven H. Kroft; Timothy S. Olson; Alix E. Seif; Gerald Wertheim; Struan F.A. Grant; Linda T. Vo; Jennifer M. Puck; Kathleen E. Sullivan; John M. Routes; Viktoria Zakharova; Anna Shcherbina; Anna Mukhina; Natasha L. Rudy; Anna C.E. Hurst; T. Prescott Atkinson; Titus J. Boggon; Hakon Hakonarson; Adam R. Abate; Joud Hajjar; Sarah K. Nicholas; James R. Lupski; James Verbsky; Ivan K. Chinn; Michael V. Gonzalez; Andrew D. Wells; Alex Marson; Gregory M.K. Poon; Neil Romberg. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. Journal of Experimental Medicine 2021, 218, 1 .

AMA Style

Carole Le Coz, David N. Nguyen, Chun Su, Brian E. Nolan, Amanda V. Albrecht, Suela Xhani, Di Sun, Benjamin Demaree, Piyush Pillarisetti, Caroline Khanna, Francis Wright, Peixin Amy Chen, Samuel Yoon, Amy L. Stiegler, Kelly Maurer, James P. Garifallou, Amy Rymaszewski, Steven H. Kroft, Timothy S. Olson, Alix E. Seif, Gerald Wertheim, Struan F.A. Grant, Linda T. Vo, Jennifer M. Puck, Kathleen E. Sullivan, John M. Routes, Viktoria Zakharova, Anna Shcherbina, Anna Mukhina, Natasha L. Rudy, Anna C.E. Hurst, T. Prescott Atkinson, Titus J. Boggon, Hakon Hakonarson, Adam R. Abate, Joud Hajjar, Sarah K. Nicholas, James R. Lupski, James Verbsky, Ivan K. Chinn, Michael V. Gonzalez, Andrew D. Wells, Alex Marson, Gregory M.K. Poon, Neil Romberg. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. Journal of Experimental Medicine. 2021; 218 (7):1.

Chicago/Turabian Style

Carole Le Coz; David N. Nguyen; Chun Su; Brian E. Nolan; Amanda V. Albrecht; Suela Xhani; Di Sun; Benjamin Demaree; Piyush Pillarisetti; Caroline Khanna; Francis Wright; Peixin Amy Chen; Samuel Yoon; Amy L. Stiegler; Kelly Maurer; James P. Garifallou; Amy Rymaszewski; Steven H. Kroft; Timothy S. Olson; Alix E. Seif; Gerald Wertheim; Struan F.A. Grant; Linda T. Vo; Jennifer M. Puck; Kathleen E. Sullivan; John M. Routes; Viktoria Zakharova; Anna Shcherbina; Anna Mukhina; Natasha L. Rudy; Anna C.E. Hurst; T. Prescott Atkinson; Titus J. Boggon; Hakon Hakonarson; Adam R. Abate; Joud Hajjar; Sarah K. Nicholas; James R. Lupski; James Verbsky; Ivan K. Chinn; Michael V. Gonzalez; Andrew D. Wells; Alex Marson; Gregory M.K. Poon; Neil Romberg. 2021. "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients." Journal of Experimental Medicine 218, no. 7: 1.

Letter to the editor
Published: 05 May 2021 in Diabetes, Obesity and Metabolism
Reads 0
Downloads 0
ACS Style

Hui‐Qi Qu; Jingchun Qu; Jonathan Bradfield; Joseph Glessner; Xiao Chang; Michael March; Frank D Mentch; Jeffrey D Roizen; John J Connolly; Patrick Sleiman; Hakon Hakonarson. Combined Application of Genetic and Polygenic Risk Score for Type 1 Diabetes Risk Prediction. Diabetes, Obesity and Metabolism 2021, 1 .

AMA Style

Hui‐Qi Qu, Jingchun Qu, Jonathan Bradfield, Joseph Glessner, Xiao Chang, Michael March, Frank D Mentch, Jeffrey D Roizen, John J Connolly, Patrick Sleiman, Hakon Hakonarson. Combined Application of Genetic and Polygenic Risk Score for Type 1 Diabetes Risk Prediction. Diabetes, Obesity and Metabolism. 2021; ():1.

Chicago/Turabian Style

Hui‐Qi Qu; Jingchun Qu; Jonathan Bradfield; Joseph Glessner; Xiao Chang; Michael March; Frank D Mentch; Jeffrey D Roizen; John J Connolly; Patrick Sleiman; Hakon Hakonarson. 2021. "Combined Application of Genetic and Polygenic Risk Score for Type 1 Diabetes Risk Prediction." Diabetes, Obesity and Metabolism , no. : 1.

Journal article
Published: 29 April 2021 in Scientific Reports
Reads 0
Downloads 0

CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16a ΔUBC mice, to investigate the loss of function of CLEC16A. The mice exhibited a neuronal phenotype including tremors and impaired gait that rapidly progressed to dystonic postures. Nerve conduction studies and pathological analysis revealed loss of sensory axons that are associated with this phenotype. Activated microglia and astrocytes were found in regions of the CNS. Several mitochondrial-related proteins were up- or down-regulated. Upregulation of interferon stimulated gene 15 (IGS15) were observed in neuronal tissues. CLEC16A expression inversely related to IGS15 expression. ISG15 may be the link between CLEC16A and downstream autoimmune, inflammatory processes. Our results demonstrate that a whole-body, inducible knockout of Clec16a in mice results in an inflammatory neurodegenerative phenotype resembling spinocerebellar ataxia.

ACS Style

Heather S. Hain; Rahul Pandey; Marina Bakay; Bryan P. Strenkowski; Danielle Harrington; Micah Romer; William W. Motley; Jian Li; Eunjoo Lancaster; Lindsay Roth; Judith B. Grinspan; Steven S. Scherer; Hakon Hakonarson. Inducible knockout of Clec16a in mice results in sensory neurodegeneration. Scientific Reports 2021, 11, 1 -14.

AMA Style

Heather S. Hain, Rahul Pandey, Marina Bakay, Bryan P. Strenkowski, Danielle Harrington, Micah Romer, William W. Motley, Jian Li, Eunjoo Lancaster, Lindsay Roth, Judith B. Grinspan, Steven S. Scherer, Hakon Hakonarson. Inducible knockout of Clec16a in mice results in sensory neurodegeneration. Scientific Reports. 2021; 11 (1):1-14.

Chicago/Turabian Style

Heather S. Hain; Rahul Pandey; Marina Bakay; Bryan P. Strenkowski; Danielle Harrington; Micah Romer; William W. Motley; Jian Li; Eunjoo Lancaster; Lindsay Roth; Judith B. Grinspan; Steven S. Scherer; Hakon Hakonarson. 2021. "Inducible knockout of Clec16a in mice results in sensory neurodegeneration." Scientific Reports 11, no. 1: 1-14.

Commentary
Published: 28 April 2021 in The Innovation
Reads 0
Downloads 0
ACS Style

Xiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick M.A. Sleiman; Hakon Hakonarson. Genetic correlations between COVID-19 and a variety of traits and diseases. The Innovation 2021, 2, 100112 .

AMA Style

Xiao Chang, Yun Li, Kenny Nguyen, Huiqi Qu, Yichuan Liu, Joseph Glessner, Patrick M.A. Sleiman, Hakon Hakonarson. Genetic correlations between COVID-19 and a variety of traits and diseases. The Innovation. 2021; 2 (2):100112.

Chicago/Turabian Style

Xiao Chang; Yun Li; Kenny Nguyen; Huiqi Qu; Yichuan Liu; Joseph Glessner; Patrick M.A. Sleiman; Hakon Hakonarson. 2021. "Genetic correlations between COVID-19 and a variety of traits and diseases." The Innovation 2, no. 2: 100112.

Journal article
Published: 27 April 2021 in Genes
Reads 0
Downloads 0

There is strong evidence for a genetic contribution to non-syndromic congenital heart defects (CHDs). However, exome- and genome-wide studies conducted at the variant and gene-level have identified few genome-wide significant CHD-related genes. Gene-set analyses are a useful complement to such studies and candidate gene-set analyses of rare variants have provided insight into the genetics of CHDs. However, similar analyses have not been conducted using data on common genetic variants. Consequently, we conducted common variant analyses of 15 CHD candidate gene-sets, using data from two common types of CHDs: conotruncal heart defects (1431 cases) and left ventricular outflow tract defects (509 cases). After Bonferroni correction for evaluation of multiple gene-sets, the cytoskeletal gene-set was significantly associated with conotruncal heart defects (βS = 0.09; 95% confidence interval (CI) 0.03–0.15). This association was stronger when analyses were restricted to the sub-set of cytoskeletal genes that have been observed to harbor rare damaging genotypes in at least two CHD cases (βS = 0.32, 95% CI 0.08–0.56). These findings add to the evidence linking cytoskeletal genes to CHDs and suggest that, for cytoskeletal genes, common variation may contribute to the risk of CHDs.

ACS Style

Fadi Musfee; A. Agopian; Elizabeth Goldmuntz; Hakon Hakonarson; Bernice Morrow; Deanne Taylor; Martin Tristani-Firouzi; W. Watkins; Mark Yandell; Laura Mitchell. Common Variation in Cytoskeletal Genes Is Associated with Conotruncal Heart Defects. Genes 2021, 12, 655 .

AMA Style

Fadi Musfee, A. Agopian, Elizabeth Goldmuntz, Hakon Hakonarson, Bernice Morrow, Deanne Taylor, Martin Tristani-Firouzi, W. Watkins, Mark Yandell, Laura Mitchell. Common Variation in Cytoskeletal Genes Is Associated with Conotruncal Heart Defects. Genes. 2021; 12 (5):655.

Chicago/Turabian Style

Fadi Musfee; A. Agopian; Elizabeth Goldmuntz; Hakon Hakonarson; Bernice Morrow; Deanne Taylor; Martin Tristani-Firouzi; W. Watkins; Mark Yandell; Laura Mitchell. 2021. "Common Variation in Cytoskeletal Genes Is Associated with Conotruncal Heart Defects." Genes 12, no. 5: 655.

Journal article
Published: 01 April 2021 in Scientific Reports
Reads 0
Downloads 0

CLEC16A is implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout (KO), Clec16a ΔUBC mice to address the role of CLEC16A loss of function. KO mice exhibited loss of adipose tissue and severe weight loss in response to defective autophagic flux and exaggerated endoplasmic reticulum (ER) stress and robust cytokine storm. KO mice were glucose tolerant and displayed a state of systemic inflammation with elevated antibody levels, including IgM, IgA, Ig2b and IgG3, significantly reduced circulating insulin levels in the presence of normal food consumption. Metabolic analysis revealed disturbances in the lipid profile, white adipose decreasing concomitantly with enhanced inflammatory response, and energy wasting. Mechanistically, endoplasmic reticulum (ER) stress triggers excessive hormone sensitive lipases (HSL) mediated lipolysis which contributes to adipose inflammation via activation of JAK-STAT, stress kinases (ERK1/2, P38, JNK), and release of multiple proinflammatory mediators. Treatment with a JAK-STAT inhibitor (tofacitinib) partially rescued the inflammatory lipodystrophic phenotype and improved survival of Clec16a ΔUBC mice by silencing cytokine release and modulating ER stress, lipolysis, mitophagy and autophagy. These results establish a mechanistic link between CLEC16A, lipid metabolism and the immune system perturbations. In summary, our Clec16a ΔUBC mouse model highlights multifaceted roles of Clec16a in normal physiology, including a novel target for weight regulation and mutation-induced pathophysiology.

ACS Style

Rahul Pandey; Marina Bakay; Bryan P. Strenkowski; Heather S. Hain; Hakon Hakonarson. JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice. Scientific Reports 2021, 11, 1 -17.

AMA Style

Rahul Pandey, Marina Bakay, Bryan P. Strenkowski, Heather S. Hain, Hakon Hakonarson. JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice. Scientific Reports. 2021; 11 (1):1-17.

Chicago/Turabian Style

Rahul Pandey; Marina Bakay; Bryan P. Strenkowski; Heather S. Hain; Hakon Hakonarson. 2021. "JAK/STAT inhibitor therapy partially rescues the lipodystrophic autoimmune phenotype in Clec16a KO mice." Scientific Reports 11, no. 1: 1-17.

Original article
Published: 30 March 2021 in American Journal of Medical Genetics Part A
Reads 0
Downloads 0

Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype–phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants. This study identifies genotype–phenotype correlations as well as race‐facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long‐term outcomes in individuals with WSS.

ACS Style

Sarah E. Sheppard; Ian M. Campbell; Margaret H. Harr; Nina Gold; Dong Li; Hans T. Bjornsson; Julie S. Cohen; Jill A. Fahrner; Ali Fatemi; Jacqueline R. Harris; Catherine Nowak; Cathy A. Stevens; Katheryn Grand; Margaret Au; John M. Graham Jr; Pedro A. Sanchez‐Lara; Miguel Del Campo; Marilyn C. Jones; Omar Abdul‐Rahman; Fowzan S. Alkuraya; Jennifer A. Bassetti; Katherine Bergstrom; Elizabeth Bhoj; Sarah Dugan; Julie D. Kaplan; Nada Derar; Karen W. Gripp; Natalie Hauser; A. Micheil Innes; Beth Keena; Neslida Kodra; Rebecca Miller; Beverly Nelson; Malgorzata J. Nowaczyk; Zuhair Rahbeeni; Shay Ben‐Shachar; Joseph T. Shieh; Anne Slavotinek; Andrew K. Sobering; Mary‐Alice Abbott; Dawn C. Allain; Louise Amlie‐Wolf; Ping Yee Billie Au; Emma Bedoukian; Geoffrey Beek; James Barry; Janet Berg; Jonathan A. Bernstein; Cheryl Cytrynbaum; Brian Hon‐Yin Chung; Sarah Donoghue; Naghmeh Dorrani; Alison Eaton; Josue A. Flores‐Daboub; Holly Dubbs; Carolyn A. Felix; Chin‐To Fong; Jasmine Lee Fong Fung; Balram Gangaram; Amy Goldstein; Rotem Greenberg; Thoa K. Ha; Joseph Hersh; Kosuke Izumi; Staci Kallish; Elijah Kravets; Pui‐Yan Kwok; Rebekah K. Jobling; Amy E. Knight Johnson; Jessica Kushner; Bo Hoon Lee; Brooke Levin; Kristin Lindstrom; Kandamurugu Manickam; Rebecca Mardach; Elizabeth McCormick; D. Ross McLeod; Frank D. Mentch; Kelly Minks; Colleen Muraresku; Stanley F. Nelson; Patrizia Porazzi; Pavel N. Pichurin; Nina N. Powell‐Hamilton; Zoe Powis; Alyssa Ritter; Caleb Rogers; Luis Rohena; Carey Ronspies; Audrey Schroeder; Zornitza Stark; Lois Starr; Joan Stoler; Pim Suwannarat; Milen Velinov; Rosanna Weksberg; Yael Wilnai; Neda Zadeh; Dina J. Zand; Marni J. Falk; Hakon Hakonarson; Elaine H. Zackai; Fabiola Quintero‐Rivera. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome. American Journal of Medical Genetics Part A 2021, 185, 1649 -1665.

AMA Style

Sarah E. Sheppard, Ian M. Campbell, Margaret H. Harr, Nina Gold, Dong Li, Hans T. Bjornsson, Julie S. Cohen, Jill A. Fahrner, Ali Fatemi, Jacqueline R. Harris, Catherine Nowak, Cathy A. Stevens, Katheryn Grand, Margaret Au, John M. Graham Jr, Pedro A. Sanchez‐Lara, Miguel Del Campo, Marilyn C. Jones, Omar Abdul‐Rahman, Fowzan S. Alkuraya, Jennifer A. Bassetti, Katherine Bergstrom, Elizabeth Bhoj, Sarah Dugan, Julie D. Kaplan, Nada Derar, Karen W. Gripp, Natalie Hauser, A. Micheil Innes, Beth Keena, Neslida Kodra, Rebecca Miller, Beverly Nelson, Malgorzata J. Nowaczyk, Zuhair Rahbeeni, Shay Ben‐Shachar, Joseph T. Shieh, Anne Slavotinek, Andrew K. Sobering, Mary‐Alice Abbott, Dawn C. Allain, Louise Amlie‐Wolf, Ping Yee Billie Au, Emma Bedoukian, Geoffrey Beek, James Barry, Janet Berg, Jonathan A. Bernstein, Cheryl Cytrynbaum, Brian Hon‐Yin Chung, Sarah Donoghue, Naghmeh Dorrani, Alison Eaton, Josue A. Flores‐Daboub, Holly Dubbs, Carolyn A. Felix, Chin‐To Fong, Jasmine Lee Fong Fung, Balram Gangaram, Amy Goldstein, Rotem Greenberg, Thoa K. Ha, Joseph Hersh, Kosuke Izumi, Staci Kallish, Elijah Kravets, Pui‐Yan Kwok, Rebekah K. Jobling, Amy E. Knight Johnson, Jessica Kushner, Bo Hoon Lee, Brooke Levin, Kristin Lindstrom, Kandamurugu Manickam, Rebecca Mardach, Elizabeth McCormick, D. Ross McLeod, Frank D. Mentch, Kelly Minks, Colleen Muraresku, Stanley F. Nelson, Patrizia Porazzi, Pavel N. Pichurin, Nina N. Powell‐Hamilton, Zoe Powis, Alyssa Ritter, Caleb Rogers, Luis Rohena, Carey Ronspies, Audrey Schroeder, Zornitza Stark, Lois Starr, Joan Stoler, Pim Suwannarat, Milen Velinov, Rosanna Weksberg, Yael Wilnai, Neda Zadeh, Dina J. Zand, Marni J. Falk, Hakon Hakonarson, Elaine H. Zackai, Fabiola Quintero‐Rivera. Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome. American Journal of Medical Genetics Part A. 2021; 185 (6):1649-1665.

Chicago/Turabian Style

Sarah E. Sheppard; Ian M. Campbell; Margaret H. Harr; Nina Gold; Dong Li; Hans T. Bjornsson; Julie S. Cohen; Jill A. Fahrner; Ali Fatemi; Jacqueline R. Harris; Catherine Nowak; Cathy A. Stevens; Katheryn Grand; Margaret Au; John M. Graham Jr; Pedro A. Sanchez‐Lara; Miguel Del Campo; Marilyn C. Jones; Omar Abdul‐Rahman; Fowzan S. Alkuraya; Jennifer A. Bassetti; Katherine Bergstrom; Elizabeth Bhoj; Sarah Dugan; Julie D. Kaplan; Nada Derar; Karen W. Gripp; Natalie Hauser; A. Micheil Innes; Beth Keena; Neslida Kodra; Rebecca Miller; Beverly Nelson; Malgorzata J. Nowaczyk; Zuhair Rahbeeni; Shay Ben‐Shachar; Joseph T. Shieh; Anne Slavotinek; Andrew K. Sobering; Mary‐Alice Abbott; Dawn C. Allain; Louise Amlie‐Wolf; Ping Yee Billie Au; Emma Bedoukian; Geoffrey Beek; James Barry; Janet Berg; Jonathan A. Bernstein; Cheryl Cytrynbaum; Brian Hon‐Yin Chung; Sarah Donoghue; Naghmeh Dorrani; Alison Eaton; Josue A. Flores‐Daboub; Holly Dubbs; Carolyn A. Felix; Chin‐To Fong; Jasmine Lee Fong Fung; Balram Gangaram; Amy Goldstein; Rotem Greenberg; Thoa K. Ha; Joseph Hersh; Kosuke Izumi; Staci Kallish; Elijah Kravets; Pui‐Yan Kwok; Rebekah K. Jobling; Amy E. Knight Johnson; Jessica Kushner; Bo Hoon Lee; Brooke Levin; Kristin Lindstrom; Kandamurugu Manickam; Rebecca Mardach; Elizabeth McCormick; D. Ross McLeod; Frank D. Mentch; Kelly Minks; Colleen Muraresku; Stanley F. Nelson; Patrizia Porazzi; Pavel N. Pichurin; Nina N. Powell‐Hamilton; Zoe Powis; Alyssa Ritter; Caleb Rogers; Luis Rohena; Carey Ronspies; Audrey Schroeder; Zornitza Stark; Lois Starr; Joan Stoler; Pim Suwannarat; Milen Velinov; Rosanna Weksberg; Yael Wilnai; Neda Zadeh; Dina J. Zand; Marni J. Falk; Hakon Hakonarson; Elaine H. Zackai; Fabiola Quintero‐Rivera. 2021. "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome." American Journal of Medical Genetics Part A 185, no. 6: 1649-1665.