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| Open AccessDeep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.
- Martin Grønbæk-Thygesen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessTracing genetic diversity captures the molecular basis of misfolding disease
Pei et al. applied Gaussian process-based machine learning to capture dynamic spatial covariance relationships managed by proteostasis to mediate cooperative folding on a residue basis as a standard model for precision disease management.
- Pei Zhao
- , Chao Wang
- & William E. Balch
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessBiallelic NAA60 variants with impaired N-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications
Most individuals with primary familial brain calcification (PFBC) remain genetically unsolved. Here the authors show that NAA60 biallelic variants cause PFBC, likely via reduced N-terminal acetylation and SLC20A2 levels with impaired phosphate uptake.
- Viorica Chelban
- , Henriette Aksnes
- & Henry Houlden
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Article
| Open AccessSNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
SNURPORTIN-1, encoded by the SNUPN gene, plays a key role in the nuclear import of spliceosomal small nuclear ribonucleoproteins, however its physiological function remains unclear. Here the authors report that recessive SNUPN mutations cause a distinct subtype of childhood muscular dystrophy and reveal SNURPORTIN-1’s role in muscle homeostasis, offering insights for new therapeutic strategies.
- Marwan Nashabat
- , Nasrinsadat Nabavizadeh
- & Nathalie Escande-Beillard
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Article
| Open AccessUnraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine
Congenital vertebral malformation has a complex genetic architecture that isn’t fully understood. Here, the authors explore the genetic architecture of congenital vertebral malformation through case-control rare variant genetic analyses and embryonic transcriptome analyses of the developing spine.
- Sen Zhao
- , Hengqiang Zhao
- & Nan Wu
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Article
| Open AccessLarge scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development
The pathobiology of heart failure (HF) is incompletely understood. The authors identify 37 circulating proteins and 5 protein modules associated with HF risk, with several demonstrating causal effects on HF, risk factors, or cardiac dysfunction by Mendelian randomization analysis.
- Amil M. Shah
- , Peder L. Myhre
- & Bing Yu
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Article
| Open AccessFatty acid synthesis suppresses dietary polyunsaturated fatty acid use
Polyunsaturated Fatty Acids (PUFA), such as omega-3 fatty acids, are recognized for their lipid lowering and anti-inflammatory properties. Here, the authors show that endogenous lipid synthesis controls the use of PUFA and thus determine the therapeutic benefit of omega-3 fatty acid supplementation.
- Anna Worthmann
- , Julius Ridder
- & Christian Schlein
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Article
| Open Accessvcfdist: accurately benchmarking phased small variant calls in human genomes
Accurately benchmarking small variant calling accuracy is critical for the continued improvement of human genome sequencing. Here, the authors show that current approaches are biased towards certain variant representations and develop a new approach to ensure consistent and accurate benchmarking, regardless of the original variant representations.
- Tim Dunn
- & Satish Narayanasamy
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Article
| Open AccessSLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling
White adipose tissue is closely associated with energy expenditure and obesity. Here, the authors show that SLC35D3 promotes white adipose tissue browning through the NOTCH1 signalling pathway and SLC35D3 may be a potential therapeutic target for obesity and related complications.
- Hongrui Wang
- , Liang Yu
- & Yibo Wang
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Article
| Open AccessSystematic analysis of paralogous regions in 41,755 exomes uncovers clinically relevant variation
Chameleolyser enables the accurate identification of genetic variants hidden within complex regions of the genome. Its application uncovers the disease-explanatory variant in 25 previously undiagnosed patients.
- Wouter Steyaert
- , Lonneke Haer-Wigman
- & Christian Gilissen
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Article
| Open AccessWhole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea
Rosacea is a common, multi-factorial chronic inflammatory skin disorder. Here authors provide evidence of genetic predisposition by whole genome sequencing and whole exome sequencing of samples from familial cases, and by recapitulating a recurrent mutation in the LRRC4 gene in a mouse model, they find that neuron-derived vasoactive intestinal peptide is an important pathogenic factor for neurogenic inflammation in rosacea.’
- Zhili Deng
- , Mengting Chen
- & Ji Li
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Article
| Open AccessDeficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.
- Asmundur Oddsson
- , Patrick Sulem
- & Daniel F. Gudbjartsson
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Article
| Open AccessVariants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
The SART3 gene encodes an RNA-binding protein critical for spliceosome function. Here, the authors find that bi-allelic variants in SART3 underlie a congenital condition characterised by neuro-developmental defects and 46,XY gonadal dysgenesis.
- Katie L. Ayers
- , Stefanie Eggers
- & Andrew H. Sinclair
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Article
| Open AccessIdentifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.
- Yiming Wu
- , Kyle Gettler
- & Yuval Itan
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Article
| Open AccessEnhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation
Heterotopic ossification is a disorder characterized by the transformation of soft tissue to bone. In this study the authors report heterotopic ossification in a child caused by enhancer hijacking at the ARHGAP36 gene, the ectopic activation by an enhancer that it not its own.
- Uirá Souto Melo
- , Jerome Jatzlau
- & Malte Spielmann
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Article
| Open AccessTEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.
- Lindsey Van Haute
- , Emily O’Connor
- & Rita Horvath
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Article
| Open AccessGenome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure
Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.
- Joel T. Rämö
- , Tuomo Kiiskinen
- & Aarno Palotie
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Article
| Open AccessA gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation
TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
- Qiaochu Wang
- , Zengge Wang
- & Wei Li
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Article
| Open AccessDominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish
Disruptions to the ER-Golgi network can lead to neurodevelopmental disorders, though our understanding of these Golgipathies remains incomplete. Here Lauri, Tartaglia and colleagues show that ARF3 mutations cause a rare pediatric neurological disorder and perform detailed molecular characterization in fish.
- Giulia Fasano
- , Valentina Muto
- & Marco Tartaglia
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Article
| Open AccessAnalysis of clinically relevant variants from ancestrally diverse Asian genomes
Clinically significant genetic variation in Asian populations is under-characterized. Here, the authors show the diversity in prevalence and spectrum of human disease and pharmacogenetic variants in a multi-ethnic Asian population.
- Sock Hoai Chan
- , Yasmin Bylstra
- & Weng Khong Lim
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Article
| Open AccessSystematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke
Mendelian randomization can be used to mimic the effects of protein-targeting drugs in a population of individuals. Here, the authors have identified potential causal proteins for stroke in a two-sample Mendelian randomization framework, providing potential stroke therapeutic targets.
- Lingyan Chen
- , James E. Peters
- & Joanna M. M. Howson
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Article
| Open AccessNatural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity
Natural Killer cells are key mediators of anti-tumour immunosurveillance and anti-viral immunity. Here, the authors map regulatory genetic variation in primary Natural Killer cells, providing new insights into their role in human health and disease.
- James J. Gilchrist
- , Seiko Makino
- & Benjamin P. Fairfax
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Article
| Open AccessThe contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
Albinism is a rare disorder often caused by high-effect rare variants in the TYR gene. Here, the authors study a large albinism cohort and find that a common variant in the TYR promoter contributes to albinism by modifying the penetrance of other common variants, demonstrating a complex genetic architecture.
- Vincent Michaud
- , Eulalie Lasseaux
- & Panagiotis I. Sergouniotis
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Article
| Open AccessCommon genetic variation associated with Mendelian disease severity revealed through cryptic phenotype analysis
The severity of rare genetic diseases often varies between individuals, but small sample sizes make it difficult to identify contributing factors. Here, the authors use biobank-scale clinical and genetic data to investigate a role for common genetic variation.
- David R. Blair
- , Thomas J. Hoffmann
- & Joseph T. Shieh
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Article
| Open AccessVariants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility
The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in ASPH, a gene encoding junctin, and validating them in animal and cell models.
- Yukari Endo
- , Linda Groom
- & James J. Dowling
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Article
| Open AccessPopulation-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene
While the consequences of homozygous loss of function variants have been studied, the effect of missense variants is less understood. Here, the authors identify pathogenic genotypes through an observed deficit of homozygous carriers of missense variants in a population, elucidating previously unexplained recessive disease and miscarriage.
- Gudny A. Arnadottir
- , Asmundur Oddsson
- & Kari Stefansson
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Article
| Open AccessA neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder
SP7 is a transcription factor required for osteoblast differentiation and bone formation. A neomorphic mutation in SP7 was found to alter DNA binding specificity, causing a complex skeletal disorder in both mice and humans.
- Julian C. Lui
- , Adalbert Raimann
- & Jeffrey Baron
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Article
| Open AccessA de novo paradigm for male infertility
Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.
- M. S. Oud
- , R. M. Smits
- & J. A. Veltman
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Article
| Open AccessIncorporating functional priors improves polygenic prediction accuracy in UK Biobank and 23andMe data sets
Incorporating functional information has shown promise for improving polygenic risk prediction of complex traits. Here, the authors describe polygenic prediction method LDpred-funct, and demonstrate its utility across 21 heritable traits in the UK Biobank.
- Carla Márquez-Luna
- , Steven Gazal
- & Alkes L. Price
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Article
| Open AccessIdentification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity
Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.
- Endika Haro
- , Florence Petit
- & Kerby C. Oberg
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Article
| Open AccessMesomelic dysplasias associated with the HOXD locus are caused by regulatory reallocations
Mesomelic dysplasia, a severe shortening and bending of the limb, has been linked to rearrangements in the HoxD cluster in humans and mice. Here the authors engineer a 1 Mb inversion including the HoxD gene cluster and use this model to provide a mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
- Christopher Chase Bolt
- , Lucille Lopez-Delisle
- & Denis Duboule
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Article
| Open AccessDeletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia
Acheiropodia is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development, but how these deletions lead to this phenotype is unknown. Here the authors use whole-genome sequencing, ChIP-seq, 4C-seq and DNA FISH to show that alterations in CTCF motifs are responsible via altered enhancer–promoter interactions.
- Aki Ushiki
- , Yichi Zhang
- & Nadav Ahituv
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Article
| Open AccessDeficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling
Sclerosing bone disorder (SBD) includes a broad spectrum of monogenic diseases characterised by increased bone density. Here, the authors describe a previously unknown SBD in four families caused by mutations in TMEM53 and demonstrate the role this protein plays in BMP signalling during bone formation.
- Long Guo
- , Aritoshi Iida
- & Shiro Ikegawa
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Article
| Open AccessAccurate imputation of human leukocyte antigens with CookHLA
Human leukocyte antigen (HLA) genes influence many immune phenotypes, however methods to impute HLA type have been limited in accuracy. Here, the authors present an HLA imputation method, CookHLA, which uses locally embedded prediction markers to adaptively impute HLA genes across a range of scenarios.
- Seungho Cook
- , Wanson Choi
- & Buhm Han
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Article
| Open AccessGWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator (AIRE).
- Daniel Eriksson
- , Ellen Christine Røyrvik
- & Eystein Sverre Husebye
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Article
| Open AccessImpaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine
eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.
- Víctor Faundes
- , Martin D. Jennings
- & Siddharth Banka
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Article
| Open AccessDetection of aberrant splicing events in RNA-seq data using FRASER
Aberrant splicing is a major contributor to rare disease, but detection accuracy using current methods is limited. Here, the authors develop an algorithm that detects aberrant splicing and intron retention events from RNA-seq data and apply it to diagnosis in mitochondrial disease.
- Christian Mertes
- , Ines F. Scheller
- & Julien Gagneur
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Article
| Open AccessPCM1 is necessary for focal ciliary integrity and is a candidate for severe schizophrenia
The role of ciliary/centriolar components in the postnatal brain is unclear. Here, the authors show via ablation of Pcm1 in mice that degenerative ciliary/centriolar phenotypes induce neuroanatomical and behavioral changes. Sequencing of PCM1 in human cohorts and zebrafish in vivo complementation suggests PCM1 mutations can contribute to schizophrenia.
- Tanner O. Monroe
- , Melanie E. Garrett
- & Nicholas Katsanis
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Article
| Open AccessLSH mediates gene repression through macroH2A deposition
The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription.
- Kai Ni
- , Jianke Ren
- & Kathrin Muegge
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Article
| Open AccessEarly-onset autoimmunity associated with SOCS1 haploinsufficiency
SOCS1 is a potent suppressor of JAK-STAT signalling responses to IFNγ and γ-chain cytokines and thereby limits inflammation. Here the authors identify and characterize heterozygous SOCS1 mutations in 10 patients from 5 unrelated families with autoimmune diseases.
- Jérôme Hadjadj
- , Carla Noemi Castro
- & Frédéric Rieux-Laucat
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Article
| Open AccessNEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease
Defective protein quality control is a key feature of neurodegeneration. Here, the authors show that mutations in Nemf/NEMF, a component of the Ribosome-associated Quality Control complex, have a neurodegenerative effect in mice and may underlie neuromuscular disease in seven unrelated families.
- Paige B. Martin
- , Yu Kigoshi-Tansho
- & Gregory A. Cox
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Article
| Open AccessMutations in COMP cause familial carpal tunnel syndrome
Familial carpal tunnel syndrome (CTS) is common, but causal genes are not characterized. Here the authors report two CTS-related mutations in two large families that impair secretion of COMP in tenocytes, leading to ER stress-induced unfolded protein response, inflammation and fibrosis in patients and mouse models.
- Chunyu Li
- , Ni Wang
- & Bo Gao
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Article
| Open AccessHuman FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells
FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.
- Marcin Łyszkiewicz
- , Natalia Ziętara
- & Christoph Klein
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Article
| Open AccessIntronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2
Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”
- Mark A. Corbett
- , Thessa Kroes
- & Jozef Gecz
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Article
| Open AccessA human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation
Roquin-1 is a posttranscriptional regulator that controls the expression of many immune-related genes such as ICOS and TNFA. Here, the authors report a homozygous R688* loss of function mutation in Roquin-1 in a patient with syndromic uncontrolled hyperinflammation associated with immune cell activation and hypercytokinemia.
- S. J. Tavernier
- , V. Athanasopoulos
- & F. Haerynck
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Article
| Open AccessContext-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele
Interleukin-7 (IL-7) is a central cytokine in T cell homeostasis. Here the authors show that allelic variation at rs6897932, an autoimmune GWAS risk allele at IL7R, regulates surface and soluble IL-7R in stimulated monocytes, indicating a function of monocytes in IL-7-related autoimmunity.
- Hussein Al-Mossawi
- , Nicole Yager
- & Benjamin P. Fairfax
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Article
| Open AccessGenome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese
Adolescent idiopathic scoliosis (AIS) is a common pediatric disease leading to spinal deformities. Here, the authors report GWAS followed by genome-wide meta-analysis in up to 79,211 Japanese individuals, identifying 20 genetic loci for AIS, 14 of which were previously unreported, and perform in vitro validation for rs1978060.
- Ikuyo Kou
- , Nao Otomo
- & Shiro Ikegawa
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Article
| Open AccessStochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases
Statistical fine-mapping to pinpoint likely causal variants in a genomic region is complicated by linkage disequilibrium (LD). Here, Asimit et al. compare stepwise and stochastic approaches to fine-mapping and propose a Bayesian multinomial stochastic search method which they apply to six immune-mediated diseases.
- Jennifer L. Asimit
- , Daniel B. Rainbow
- & Chris Wallace