Publications by authors named "Daniel Howrigan"

We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4× mean depth) and deep whole exome (30-40× mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations.

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Data within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank. These factors recapitulate known disease classifications, disentangle elements of socioeconomic status, highlight the relevance of psychiatric constructs to health and improve measurement of pro-health behaviours.

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Genomic scientists have long been promised cheaper DNA sequencing, but deep whole genomes are still costly, especially when considered for large cohorts in population-level studies. More affordable options include microarrays + imputation, whole exome sequencing (WES), or low-pass whole genome sequencing (WGS) + imputation. WES + array + imputation has recently been shown to yield 99% of association signals detected by WGS.

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Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance.

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Article Synopsis
  • Genome-wide association studies have identified many common genetic variants tied to human diseases, but the exploration of rare genetic variations has been limited.
  • This study analyzes exome-sequencing data from 394,841 individuals in the UK Biobank to assess the impact of rare coding variations across 4,529 phenotypes, linking genetic associations to their frequency and potential harmfulness.
  • The findings contribute to our understanding of genetic factors in health and disease, offering a public dataset and tools like the Genebass browser for researchers to investigate rare variant associations.
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  • ADHD is a common neurodevelopmental disorder with a strong genetic basis, as shown in a large study involving 38,691 individuals with the disorder compared to 186,843 controls.
  • Researchers found 27 significant genomic regions linked to ADHD, with many genes related to early brain development and certain brain cell types, suggesting a biological basis for the disorder.
  • The study also highlighted that many genetic factors influencing ADHD overlap with other psychiatric conditions and are correlated with cognitive challenges, particularly in areas like attention and reasoning.
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Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e.

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We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8.

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  • * Researchers discovered 287 genomic regions associated with schizophrenia, emphasizing genes specifically active in excitatory and inhibitory neurons, and identified 120 key genes potentially responsible for these associations.
  • * The findings highlight important biological processes related to neuronal function, suggesting overlaps between common and rare genetic variants in both schizophrenia and neurodevelopmental disorders, ultimately aiding future research on these conditions.
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  • A meta-analysis of whole exomes from 24,248 schizophrenia cases and 97,322 controls identified ultra-rare coding variants (URVs) linked to schizophrenia risk across 10 significant genes.
  • Some of these genes are heavily expressed in the brain and are involved in synapse formation, pointing to a connection between glutamate system dysfunction and schizophrenia.
  • Additionally, there's an overlap in rare variant risks shared with other disorders like autism and epilepsy, suggesting that both common and rare genetic factors contribute to the same biological processes underlying schizophrenia.
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Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk.

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Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls.

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  • Protein-coding de novo mutations (DNMs) contribute to neurodevelopmental disorders, but their role in schizophrenia (SCZ) risk is considered modest based on this study.
  • Analysis of 2,772 SCZ-affected individuals revealed that while the overall DNM burden was modest, certain genes associated with SCZ were found to be highly expressed in the brain and overlapped with those linked to other neurodevelopmental disorders.
  • None of the individual genes reached exome-wide significance, but 16 genes showed a significantly higher than expected rate of protein-truncating DNMs, indicating that larger studies are needed to fully understand the genetic risks for SCZ.
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To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS.

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  • A correction has been issued for the paper mentioned.
  • Readers can find this correction through a link provided at the top of the original paper.
  • It's important to review the correction for accurate information.
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There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown.

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Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes.

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Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci.

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Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD.

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Objective: Both rare copy number variants (CNVs) and common single-nucleotide polymorphisms (SNPs) contribute to liability to schizophrenia, but their etiological relationship has not been fully elucidated. The authors evaluated an additive model whereby risk of schizophrenia requires less contribution from common SNPs in the presence of a rare CNV, and tested for interactions.

Method: Genetic data from 21,094 case subjects with schizophrenia and 20,227 control subjects from the Psychiatric Genomics Consortium were examined.

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Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power. A central challenge for joint analysis is that different WGS data processing pipelines cause substantial differences in variant calling in combined datasets, necessitating computationally expensive reprocessing.

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Article Synopsis
  • * They tested about 1.5 million genetic variants using various models, identifying 16 significant single variants and 19 associated genes, which were then replicated in independent datasets to confirm their findings.
  • * Notably, they found new genetic variants in genes linked to Alzheimer's, including the immunoglobulin gene IGHG3 and the novel regulatory genes AC099552.4 and ZNF655, highlighting the potential role of gene regulation in the development of the disease. *
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Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort.

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