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The genetic architecture of multimodal human brain age
The biological basis of brain aging is not well understood, but it has implications for human health. Here, the authors explore the genetic basis of human brain aging, finding genetic variants, genes and potential causal relationships with disease.
- Junhao Wen
- , Bingxin Zhao
- & Christos Davatzikos
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| Open Access
Genomic malaria surveillance of antenatal care users detects reduced transmission following elimination interventions in Mozambique
Routine sampling of pregnant women at first antenatal care (ANC) visits could be used for malaria surveillance. Here, the authors compare the genetic structure of Plasmodium falciparum parasite populations between samples from first ANC users and children from the community in Mozambique, and show that it can inform about changes in transmission beyond epidemiological data.
- Nanna Brokhattingen
- , Glória Matambisso
- & Alfredo Mayor
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Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Children born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight
Assisted reproduction increases low birthweight risk in children. This study finds a mitochondrial DNA genotype that is more common in ART children, associates to birthweight and that is linked to maternal ageing and to ovarian stimulation.
- Joke Mertens
- , Florence Belva
- & Claudia Spits
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A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1
In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.
- Ling Hai
- , Dirk C. Hoffmann
- & Tobias Kessler
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Pangenome graphs improve the analysis of structural variants in rare genetic diseases
A pangenomic approach, where genome sequences are related to each other in a graph, facilitates analysis of genomic variation between individuals. Here, the authors explore the benefits of using such an approach to characterize structural variation (e.g., deletions or duplications of more than 50 base pairs) in a rare disease cohort.
- Cristian Groza
- , Carl Schwendinger-Schreck
- & Tomi Pastinen
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Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression
Complement factor H-related 4 protein (FHR-4) has been implicated in the pathophysiology of age-related macular degeneration (AMD). Here, in contrast, the authors find that levels of FHR-4 in plasma or ocular tissue do not appear to influence susceptibility to AMD or its course of progression, questioning whether modulation of FHR-4 is likely to be an effective therapeutic strategy.
- M. A. Zouache
- , B. T. Richards
- & G. S. Hageman
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Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering
Many diseases can display distinct brain imaging phenotypes across individuals, potentially reflecting disease subtypes. However, biological interpretability is limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Here, the authors describe a deep-learning method that links imaging phenotypes with genetic factors, thereby conferring genetic correlations to the disease subtypes.
- Zhijian Yang
- , Junhao Wen
- & Christos Davatzikos
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Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension
Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ, COG6 and ZNF678.
- Anna Ulrich
- , Yukyee Wu
- & Christopher J. Rhodes
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Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Prostate cancer genetic risk and associated aggressive disease in men of African ancestry
Most genetic studies for prostate cancer have been performed outside the context of Sub-Saharan Africa. Here, the authors interrogate 247,780 exomic variants for 798 Black South African men and identify genes associated with aggressive disease.
- Pamela X. Y. Soh
- , Naledi Mmekwa
- & Vanessa M. Hayes
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SLC35D3 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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Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.
- Shujuan Zhao
- , Kedous Y. Mekbib
- & Kristopher T. Kahle
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Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape
The genetic architecture of normal-range cranial vault shape in humans is poorly understood. Here, the authors extract cranial vault shape from MRI and conduct a multi-ancestry GWAS, identifying 30 independently associated genomic loci of which 29 are novel.
- Seppe Goovaerts
- , Hanne Hoskens
- & Peter Claes
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Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease
Thyroid hormones play a critical role in regulation of multiple physiological functions. Here the authors via meta-analyses and detailed variant-to-gene mapping strategies implicate novel genes, pathways and associations for thyroid function and disease.
- Alexander T. Williams
- , Jing Chen
- & Catherine John
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Telomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1
Telomeres are the protective caps of the chromosomes, which shorten with age. Smoom and colleagues developed a mouse strain with human-size telomeres. This mouse, termed Telomouse, is therefore an invaluable tool for studying human aging and cancer.
- Riham Smoom
- , Catherine Lee May
- & Yehuda Tzfati
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MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice
Autosomal dominant tubulointerstitial kidney disease (ADTKD) due to uromodulin mutations is a hereditary kidney disease causing renal fibrosis. Here, the authors show that mesencephalic astrocyte-derived neurotrophic factor can improve defective autophagy/mitophagy and decrease renal scarring in ADTKD.
- Yeawon Kim
- , Chuang Li
- & Ying Maggie Chen
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ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
Raynaud’s phenomenon is a common vasospastic disorder, but the genetic origins of the condition are not well understood. Here, the authors find common genetic variants associated with Raynaud’s phenomenon, and find genes putatively involved in the disorder.
- Sylvia Hartmann
- , Summaira Yasmeen
- & Claudia Langenberg
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Immunosuppression causes dynamic changes in expression QTLs in psoriatic skin
Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. Here, the authors investigate the genetic basis of gene expression in skin biopsies from psoriasis patients and interactions with inflammation to better understand mechanisms of the disease.
- Qian Xiao
- , Joseph Mears
- & Soumya Raychaudhuri
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Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.
- Yun Soo Hong
- , Stephanie L. Battle
- & Dan E. Arking
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Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration
Here, the authors investigate the genetic basis of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration, identifying 84 independent significant risk loci for short sleep and 1 locus for long sleep, and causal associations between sleep and psychiatric traits.
- Isabelle Austin-Zimmerman
- , Daniel F. Levey
- & Joel Gelernter
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Shared and distinct genetic etiologies for different types of clonal hematopoiesis
Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH.
- Derek W. Brown
- , Liam D. Cato
- & Mitchell J. Machiela
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Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families
Despite large sequencing and data sharing efforts it often remains challenging to provide a genetic diagnosis for individuals with suspected Mendelian (single-gene) disorders. Here, the authors describe their experiences in identifying likely causal genetic variants in thousands of families and highlight the need to consider a wide range of challenges rather than a narrow focus on sequencing technologies.
- Lama AlAbdi
- , Sateesh Maddirevula
- & Fowzan S. Alkuraya
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A versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets
Identification of gene-by-environment interactions is crucial to understand the interplay of environmental effects on complex traits. Here, the authors present MonsterLM, a method for estimating the proportion of trait variance explained by gene-by-environment interactions in a fast, unbiased manner on biobank-scale datasets.
- Matteo Di Scipio
- , Mohammad Khan
- & Guillaume Paré
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Convergent somatic evolution commences in utero in a germline ribosomopathy
Shwachman-Diamond Syndrome (SDS) is an inherited ribosome assembly disorder that increases the risk for haematopoietic malignancies. Here, the authors analysed clonal selection and evolution in SDS by sequencing patient-derived haematopoietic stem/progenitor cell colonies and exploring the function of key drivers in model organisms.
- Heather E. Machado
- , Nina F. Øbro
- & Alan J. Warren
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Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits
Many genetic variants have been associated with human traits, but the mechanism is often unknown. Here, the authors integrate local and distal genetic associations with multi-omics datasets to provide a roadmap to understand the underlying mechanisms of GWAS variants on complex traits.
- Andrew A. Brown
- , Juan J. Fernandez-Tajes
- & Ana Viñuela
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APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants
APOGEE 2 is a machine-learning tool for assessing the fragility of the mitochondrial genome, evaluating genetic variant pathogenicity and ultimately enhancing our understanding of the clinical heterogeneity of mitochondrial genetic diseases.
- Salvatore Daniele Bianco
- , Luca Parca
- & Tommaso Mazza
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Elucidation of the low-expressing erythroid CR1 phenotype by bioinformatic mining of the GATA1-driven blood-group regulome
This study provides a systematic approach to explore how blood group expression is regulated by transcription factors. As proof-of-principle, the genetic basis underlying the very low levels of CR1 on red cells of the Helgeson phenotype is explained.
- Ping Chun Wu
- , Yan Quan Lee
- & Martin L. Olsson
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Genome-wide association studies reveal novel loci associated with pyrethroid and organophosphate resistance in Anopheles gambiae and Anopheles coluzzii
Insecticide resistance in mosquitoes threatens the success of malaria control programmes. This study found that in different populations of a malaria mosquito species in West Africa, resistance is associated with different genes or different mutations in the same set of genes.
- Eric R. Lucas
- , Sanjay C. Nagi
- & David Weetman
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Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape
Invasive extravillous trophoblast cells are a key feature of placentation and successful pregnancy. Here, the authors identify transcription factors and regulatory mechanisms critical for extravillous trophoblast cell lineage development.
- Kaela M. Varberg
- , Esteban M. Dominguez
- & Elin Grundberg
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Genetic risk, adherence to healthy lifestyle and acute cardiovascular and thromboembolic complications following SARS-COV-2 infection
Cardiovascular and thromboembolic events (CVE) are common among hospitalised COVID-19 patients and are causes of many COVID-19-related deaths. Here, the authors examine whether genetic predisposition and lifestyle factors are associated with the risk of post-COVID-19 CVE using data from UK Biobank.
- Junqing Xie
- , Yuliang Feng
- & Daniel Prieto-Alhambra
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| Open Access
Genetic insights into resting heart rate and its role in cardiovascular disease
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.
- Yordi J. van de Vegte
- , Ruben N. Eppinga
- & Pim van der Harst
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Causal associations between cardiorespiratory fitness and type 2 diabetes
Being fit has been linked to a lower risk of type 2 diabetes, but it is unclear whether this relationship is causal. Using large scale studies with genetic data and measurements of cardiorespiratory fitness, the authors show evidence that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity.
- Lina Cai
- , Tomas Gonzales
- & Nicholas J. Wareham
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Deficit 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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Variants 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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| Open Access
South Asian medical cohorts reveal strong founder effects and high rates of homozygosity
South Asia is home to almost 2 billion people but is extremely underrepresented in human genetics. This study uses genomes from ~5,000 South Asians to characterize genetic variation and help facilitate future South Asian genetic studies.
- Jeffrey D. Wall
- , J. Fah Sathirapongsasuti
- & Andrew S. Peterson
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| Open Access
Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups
Here, the authors assess performance and limitations to polygenic risk scores in different race/ethnic groups. They find that polygenic risk score performance improves with diverse training data, and a better understanding of varying genetic backgrounds, social and environmental factors, and gene-environment interactions, is needed to enhance PRS performance for all groups.
- Nuzulul Kurniansyah
- , Matthew O. Goodman
- & Tamar Sofer
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| Open Access
Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation
Graft-versus-leukemia reactions are required for the eradication of myeloid malignancies after allogeneic hematopoietic cell transplantation. However, treatment efficacy is variable, depending on the immunological response. Here the authors show that dysfunction of HLA heterogeneity is associated with post-transplant leukemia relapse.
- Simona Pagliuca
- , Carmelo Gurnari
- & Jaroslaw P. Maciejewski
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| Open Access
High-throughput single nucleus total RNA sequencing of formalin-fixed paraffin-embedded tissues by snRandom-seq
Formalin-fixed paraffin-embedded (FFPE) tissues constitute a vast and valuable patient material bank, but single nucleus RNAseq using such tissues is challenging. Here the authors develop a droplet-based method called snRandom-seq for high-throughput and sensitive single nucleus RNA-seq of FFPE samples.
- Ziye Xu
- , Tianyu Zhang
- & Yongcheng Wang
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| Open Access
TEFM 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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| Open Access
Genetic correlates of vitamin D-binding protein and 25-hydroxyvitamin D in neonatal dried blood spots
In this study the authors measure the concentration of 25-hydroxyvitamin D and vitamin D binding protein (DBP) in 65,589 neonatal dried blood samples. Findings from further analyses include that the genetic correlates of DBP concentration predict the risk of vitamin D deficiency.
- Clara Albiñana
- , Zhihong Zhu
- & John J. McGrath
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| Open Access
Integrative genetic analysis illuminates ALS heritability and identifies risk genes
ALS is somewhat heritable, but the genetic basis is not completely understood. Here, the authors identify alterations in splicing in neurons associated with amyotrophic lateral sclerosis and uncover several associated genetic loci, with a potential link to nuclear pore defects.
- Salim Megat
- , Natalia Mora
- & Luc Dupuis
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| Open Access
Genome-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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| Open Access
Deciphering genetic causes for sex differences in human health through drug metabolism and transporter genes
Little is known about the causes of sex differences in disease prevalence and treatment outcomes. Here, the authors study the interaction between drug metabolism enzymes and transporters genes and sex in complex human traits to uncover sex differences in the genetic regulation of gene expression, serum biomarkers, and metabolism of drugs.
- Yingbo Huang
- , Yuting Shan
- & R. Stephanie Huang
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| Open Access
Diverse monogenic subforms of human spermatogenic failure
The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.
- Liina Nagirnaja
- , Alexandra M. Lopes
- & Donald F. Conrad
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| Open Access
A method to build extended sequence context models of point mutations and indels
The mutation rate at any specific position in the human genome depends on sequence context. Here, the authors develop a method for predicting mutation rates of point mutations and indels based on sequence context; the results can be used to find genes where de novo mutations cause disease and genes under strong selective constraint.
- Jörn Bethune
- , April Kleppe
- & Søren Besenbacher
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| Open Access
Nasal DNA methylation at three CpG sites predicts childhood allergic disease
Accurate prediction of the onset of childhood allergy is important to clarify the difference between various respiratory diseases. Here the authors propose that the methylation status of three sites in nasal DNA predicts the onset of childhood allergy which may aid diagnosis and monitoring.
- Merlijn van Breugel
- , Cancan Qi
- & Cheng-Jian Xu
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| Open Access
Pleiotropic genetic architecture and novel loci for C-reactive protein levels
Chronic inflammation and lipometabolism share many causal genes and possibly pathways. Here, the authors use a multi-trait GWAS approach to study shared genetic determinants of low-grade inflammation, measured by C-reactive protein (CRP), and closely linked lipid and metabolic pathways.
- Fotios Koskeridis
- , Evangelos Evangelou
- & Ioanna Tzoulaki
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| Open Access
Analysis 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
The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease