Biology subjects

Daly, M.

Publications and source records attributed to Daly, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2019

An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease

Multivariate methods are known to increase the statistical power of association detection, but they have lacked essential follow-up analysis tools necessary for understanding the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate regression coefficients which are lacking from multivariate results. Our method overcomes this problem by using Canonical Correlation Analysis to turn each multivariate association into its optimal univariate Linear Combination Phenotype (LCP). This enables an LCP-GWAS, which in turn generates the statistics required for follow-up analyses. We implemented our method on 12 highly correlated inflammatory biomarkers in a Finnish population-based study. Altogether, we identified 11 associations, four of which (F5, ABO, C1orf140 and PDGFRB) were not detected by biomarker-specific analyses. Fine-mapping identified 19 signals within the 11 loci and driver trait analysis determined the traits contributing to the associations. A phenome-wide association study on the 19 putative causal variants from the signals in 176,899 individuals from the FinnGen study revealed 53 disease associations (p < 1x10-4). Several reported pQTLs in the 11 loci provided orthogonal evidence for the biologically relevant functions of the putative causal variants. Our novel multivariate analysis workflow provides a powerful addition to standard univariate GWAS analyses by enabling multivariate GWAS follow-up and thus promoting the advancement of powerful multivariate methods in genomics.

genetics↗

bioRxiv2019

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan

Human genetics seeks a way to improve human health on a global scale. Expectations are running high for polygenic risk scores (PRSs) to be translated into clinical practice to predict an inborn susceptibility to health risks. While risk stratification based on PRS is one way to promote population health, a strategy to utilize genetics to prioritize modifiable risk factors and biomarkers driving heath outcome is also warranted. To this end, here we utilized PRSs to comprehensively investigate the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898). First, we conducted genome-wide association studies for 45 quantitative clinical phenotypes, constructed the individual PRSs, and associated them with the age at death of 179,066 participants in BioBank Japan. The PRSs revealed that the genetic susceptibility of high systolic blood pressure (sBP) was strongly associated with a shorter lifespan (hazard ratio [HR] = 1.03, P = 1.4x10-7). Next, we sought to replicate these associations in individuals of European ancestry in UK Biobank (n = 361,194) and FinnGen (n = 135,638). Among the investigated traits, the individuals with higher blood pressure-related PRSs were trans-ethnically associated with a shorter lifespan (HR = 1.03, Pmeta = 3.9x10-13 for sBP) and parental lifespan (HR = 1.06, PUKBB = 2.0x10-86 for sBP). Further, our trans-biobank study identified additional complex traits associated with lifespan (e.g., obesity, height, serum lipids, and platelet counts). Of them, obesity-related traits showed strikingly heterogeneous effects on lifespan between Japanese and European populations (Pheterogeneity = 9.5x10-8 for body mass index). Through trans-ethnic biobank collaboration, we elucidated the novel value of the PRS study in genetics-driven prioritization of risk factors and biomarkers which can be medically intervened to improve population health.

genetics↗

bioRxiv2019

Meta-analysis of Scandinavian Schizophrenia Exomes

Rare genetic variants may play a prominent role in schizophrenia. We report on the to date largest whole exome sequencing study of schizophrenia case-control samples from related populations and combine with other available sequence data, analysing in total 34,084 individuals (14,302 cases). Three genes showed significant association at FDR < 0.10 (SETD1A, TAF13 and MKI67) and gene-set analyses highlighted the involvement of the synaptome and excitatory neurons, and demonstrated shared architecture with high-functioning autism.

genetics↗

bioRxiv2019

Cross-disorder GWAS meta-analysis for Attention Deficit/Hyperactivity Disorder, Autism Spectrum Disorder, Obsessive Compulsive Disorder, and Tourette Syndrome

Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Obsessive-Compulsive Disorder (OCD), and Tourette Syndrome (TS) are among the most prevalent neurodevelopmental psychiatric disorders of childhood and adolescence. High comorbidity rates across these four disorders point toward a common etiological thread that could be connecting them across the repetitive behaviors-impulsivity-compulsivity continuum. Aiming to uncover the shared genetic basis across ADHD, ASD, OCD, and TS, we undertake a systematic cross-disorder meta-analysis, integrating summary statistics from all currently available genome-wide association studies (GWAS) for these disorders, as made available by the Psychiatric Genomics Consortium (PGC) and the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). We present analysis of a combined dataset of 93,294 individuals, across 6,788,510 markers and investigate associations on the single-nucleotide polymorphism (SNP), gene and pathway levels across all four disorders but also pairwise. In the ADHD-ASD-OCD-TS cross disorder GWAS meta-analysis, we uncover in total 297 genomewide significant variants from six LD (linkage disequilibrium) -independent genomic risk regions. Out of these genomewide significant association results, 199 SNPs, that map onto four genomic regions, show high posterior probability for association with at least three of the studied disorders (m-value>0.9). Gene-based GWAS meta-analysis across ADHD, ASD, OCD, and TS identified 21 genes significantly associated under Bonferroni correction. Out of those, 15 could not be identified as significantly associated based on the individual disorder GWAS dataset, indicating increased power in the cross-disorder comparisons. Cross-disorder tissue-specificity analysis implicates the Hypothalamus-Pituitary-Adrenal axis (stress response) as possibly underlying shared pathophysiology across ADHD, ASD, OCD, and TS. Our work highlights genetic variants and genes that may contribute to overlapping neurobiology across the four studied disorders and highlights the value of re-defining the framework for the study across this spectrum of highly comorbid disorders, by using transdiagnostic approaches.

genetics↗

bioRxiv2019

Polygenic and clinical risk scores and their impact on age at onset of cardiometabolic diseases and common cancers

BackgroundPolygenic risk scores (PRS) have shown promise in predicting susceptibility to common diseases. However, the extent to which PRS and clinical risk factors act jointly and identify high-risk individuals for early onset of disease is unknown.\n\nMethodsWe used large-scale biobank data (the FinnGen study; n=135,300), with up to 46 years of prospective follow-up, and the FINRISK study with standardized clinical risk factor measurements to build genome-wide PRSs with >6M variants for coronary heart disease (CHD), type 2 diabetes (T2D), atrial fibrillation (AF), and breast and prostate cancer. We evaluated their associations with first disease events, age at disease onset, and impact together with routinely used clinical risk scores for predicting future disease.\n\nResultsCompared to the 20-80th percentiles, a PRS in the top 2.5% translated into hazard ratios (HRs) for incident disease ranging from 2.03 to 4.28 (p-values 1.96x10-59 to <1.00x10-100) and the bottom 2.5% into HRs ranging from 0.20 to 0.61. The estimated difference in age at disease onset between top and bottom 2.5% of PRSs was 6 to 13 years. Among early-onset cases, 21.3-32.9% had a PRS in the highest decile and in CHD and AF.\n\nConclusionsThe properties of PRS were similar in all five diseases. PRS identified a considerable proportion early-onset cases, and for all ages the performance of PRS was comparable to established clinical risk scores. These findings warrant further clinical studies on application of polygenic risk information for stratified screening or for guiding lifestyle and preventive medical interventions.

genomics↗

bioRxiv2019

Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data in UK Biobank and FinnGen to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through protein-altering variant association analysis we find a missense variant in UK Biobank (rs28991009 (MAF=0.8%) genotyped in 81,527 individuals with measured IOP and an independent set of 4,269 glaucoma patients and 251,355 controls) that significantly lowers IOP ({beta} = -0.73 mmHg for heterozygotes, -2.96 mmHg for homozygotes, P = 1 x 10-13) and is associated with 34% reduced risk of glaucoma (P = 0.005). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.1%), which was genotyped in 5,177 glaucoma patients and 130,461 controls and is associated with 30% lower glaucoma risk (P = 1 x 10-9). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.002), suggesting the protective mechanism likely resides in the loss of an interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma

genetics↗

bioRxiv2019

Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels

Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice.

genetics↗

bioRxiv2019

Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects

Rare and large copy number variants (CNVs) around known genomic hotspots are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.

genetics↗

bioRxiv2019

Identification of pathogenic variant enriched regions across genes and gene families

Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2,871 gene family protein sequence alignments involving 9,990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 65,034 missense variants from patients. With this gene family approach, we identified 398 regions enriched for patient variants spanning 33,887 amino acids in 1,058 genes. As a comparison, testing the same genes individually we identified less patient variant enriched regions involving only 2,167 amino acids and 180 genes. Next, we selected de novo variants from 6,753 patients with neurodevelopmental disorders and 1,911 unaffected siblings, and observed a 5.56-fold enrichment of patient variants in our identified regions (95% C.I. =2.76-Inf, p-value = 6.66x10-8). Using an independent ClinVar variant set, we found missense variants inside the identified regions are 111-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 111.48, 95% C.I = 68.09-195.58, p-value < 2.2e-16). All patient variant enriched regions identified (PERs) are available online through a user-friendly platform for interactive data mining, visualization and download at http://per.broadinstitute.org. In summary, our gene family burden analysis approach identified novel patient variant enriched regions in protein sequences. This annotation can empower variant interpretation.

genetics↗

bioRxiv2019

RICOPILI: Rapid Imputation for COnsortias PIpeLIne

MotivationGenome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open sourced Perl-based pipeline was developed to address the challenges of rapidly processing large scale multi-cohort GWAS studies including quality control, imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing (HPC) environments.\n\nSummaryRICOPILI was created as the Psychiatric Genomics Consortium (PGC) pipeline for GWAS and has been adopted by other users. The pipeline features i) technical and genomic quality control in case-control and trio cohorts ii) genome-wide phasing and imputation iv) association analysis v) meta-analysis vi) polygenic risk scoring and vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all of the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work.\n\nAvailability and ImplementationRICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL: https://sites.google.com/a/broadinstitute.org/RICOPILI/home\n\nContactsripke@broadinstitute.org\n\nSupplementary informationSupplementary data are available.

genetics↗

bioRxiv2019

Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

PurposeWe aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting.\n\nMethodsWe analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6,994 panels to other 8,588 recently published panels as well as exome-wide de novo variants in 1,942 individuals with NDD+E and 10,937 controls.\n\nResultsGenes with highest frequencies of ultra-rare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A and STXBP1, concordant with the two other epilepsy cohorts we investigated. Only 46% of the analysed 262 dominant and X-linked panel genes contained ultra-rare variants in patients. Among genes with contradictory evidence of association with epilepsy CACNB4, CLCN2, EFHC1, GABRD, MAGI2 and SRPX2 showed equal frequencies in cases and controls.\n\nConclusionWe show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultra-rare variants in individuals with NDD+E to the community.

genetics↗

bioRxiv2019

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease

Analyzing 5770 all-cause cirrhosis cases and 572,850 controls from seven cohorts, we identify a missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.88, p=2.1*10-8). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.012 SD, 1.4*10-8), alkaline phosphatase (-0.019 SD, 6.6*10-9), total cholesterol (-0.037 SD, p=1*10-18) and LDL cholesterol (-0.035 SD, p=7.3*10-16). Carriers of rare protein-truncating variants in MARC1 had lower liver enzyme levels, cholesterol levels, and reduced odds of liver disease (OR 0.19, p= 0.04) suggesting that deficiency of the MARC1 enzyme protects against cirrhosis.

genomics↗

bioRxiv2019

Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinsons disease

Human genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinsons disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

genomics↗

bioRxiv2019

Phylogenetic relationships among the clownfish-hosting sea anemones

The clownfish-sea anemone symbiosis has been a model system for understanding fundamental evolutionary and ecological processes. However, our evolutionary understanding of this symbiosis comes entirely from studies of clownfishes. A holistic understanding of a model mutualism requires systematic, biogeographic, and phylogenetic insight into both partners. Here, we conduct the largest phylogenetic analysis of sea anemones (Order Actiniaria) to date, with a focus on expanding the biogeographic and taxonomic sampling of the 10 nominal clownfish-hosting species. Using a combination of mtDNA and nuDNA loci we test 1) the monophyly of each clownfish-hosting family and genus, 2) the current anemone taxonomy that suggests symbioses with clownfishes evolved multiple times within Actiniaria, and 3) whether, like the clownfishes, there is evidence that host anemones have a Coral Triangle biogeographic origin. Our phylogenetic reconstruction demonstrates widespread poly-and para-phyly at the family and genus level, particularly within the family Stichodactylidae and genus Sticodactyla, and suggests that symbioses with clownfishes evolved minimally three times within sea anemones. We further recover evidence for a Tethyan biogeographic origin for some clades. Our data provide the first evidence that clownfish and some sea anemone hosts have different biogeographic origins, and that there may be cryptic species of host anemones. Finally, our findings reflect the need for a major taxonomic revision of the clownfish-hosting sea anemones.

evolutionary biology↗

bioRxiv2018

A platform for case-control matching enables association studies without genotype sharing

Acquiring a sufficiently powered cohort of control samples can be time consuming or, sometimes, impossible. Accordingly, an ability to leverage control samples that were already collected and sequenced elsewhere could dramatically improve power in all genetic association studies. However, since majority of the genotyped and sequenced human DNA samples to date are subject to strict data sharing regulations, large-scale sharing of, in particular, control samples is extremely challenging. Using insights from image recognition, we developed a method allowing selection of the best-matching controls in an external pool of samples that is compliant with personal genotype data protection restrictions. Our approach uses singular value decomposition of the matrix of case genotypes to rank controls in another study by similarity to cases. We demonstrate that this recovers an accurate case-control association analysis for both ultra-rare and common variants and implement and provide online access to a library of ~17,000 controls that enables association studies for case cohorts lacking control subjects.

genetics↗

bioRxiv2018

Reduced representation sequencing for symbiotic anthozoans: are reference genomes necessary to eliminate endosymbiont contamination and make robust phylogeographic inference?

Anthozoan cnidarians form the backbone of coral reefs. Their success relies on endosymbiosis with photosynthetic dinoflagellates in the family Symbiodiniaceae. Photosymbionts represent a hurdle for researchers using population genomic techniques to study these highly imperiled and ecologically critical species because sequencing datasets harbor unknown mixtures of anthozoan and photosymbiont loci. Here we use range-wide sampling and a double-digest restriction-site associated DNA sequencing (ddRADseq) of the sea anemone Bartholomea annulata to explore how symbiont loci impact the interpretation of phylogeographic patterns and population genetic parameters. We use the genome of the closely related Exaiptasia diaphana (previously Aiptasia pallida) to create an anthozoan-only dataset from a genomic dataset containing both B. annulata and its symbiodiniacean symbionts and then compare this to the raw, holobiont dataset. For each, we investigate spatial patterns of genetic diversity and use coalescent model-based approaches to estimate demographic history and population parameters. The Florida Straits are the only phylogeographic break we recover for B. annulata, with divergence estimated during the last glacial maximum. Because B. annulata hosts multiple members of Symbiodiniaceae, we hypothesize that, under moderate missing data thresholds, de novo clustering algorithms that identify orthologs across datasets will have difficulty identifying shared non-coding loci from the photosymbionts. We infer that, for anthozoans hosting diverse members of Symbiodinaceae, clustering algorithms act as de facto filters of symbiont loci. Thus, while at least some photosymbiont loci remain, these are swamped by orders of magnitude greater numbers of anthozoan loci and thus represent genetic \"noise,\" rather than contributing genetic signal.

genomics↗

bioRxiv2018

Genomic signatures of sympatric speciation with historical and contemporary gene flow in a tropical anthozoan

Sympatric diversification is increasingly thought to have played an important role in the evolution of biodiversity around the globe. However, an in situ sympatric origin for co-distributed taxa is difficult to demonstrate empirically because different evolutionary processes can lead to similar biogeographic outcomes-especially in ecosystems with few hard barriers to dispersal that can facilitate allopatric speciation followed by secondary contact (e.g. marine habitats). Here we use a genomic (ddRADseq), model-based approach to delimit a cryptic species complex of tropical sea anemones that are co-distributed on coral reefs throughout the Tropical Western Atlantic. We use coalescent simulations in fastsimcoal2 to test competing diversification scenarios that span the allopatric-sympatric continuum. We recover support that the corkscrew sea anemone Bartholomea annulata (Le Sueur, 1817) is a cryptic species complex, co-distributed throughout its range. Simulation and model selection analyses suggest these lineages arose in the face of historical and contemporary gene flow, supporting a sympatric origin, but an alternative secondary contact model also receives appreciable model support. Leveraging the genome of Exaiptasia pallida we identify five loci under divergent selection between cryptic B. annulata lineages that fall within mRNA transcripts or CDS regions. Our study provides a rare empirical, genomic example of sympatric speciation in a tropical anthozoan-a group that includes reef-building corals. Finally, these data represent the first range-wide molecular study of any tropical sea anemone, underscoring that anemone diversity is under described in the tropics, and highlighting the need for additional systematic studies into these ecologically and economically important species.

evolutionary biology↗

bioRxiv2018

Signals of polygenic adaptation on height have been overestimated due to uncorrected population structure in genome-wide association studies

Genetic predictions of height differ among human populations and these differences are too large to be explained by genetic drift. This observation has been interpreted as evidence of polygenic adaptation. Differences across populations were detected using SNPs genome-wide significantly associated with height, and many studies also found that the signals grew stronger when large numbers of subsignificant SNPs were analyzed. This has led to excitement about the prospect of analyzing large fractions of the genome to detect subtle signals of selection and claims of polygenic adaptation for multiple traits. Polygenic adaptation studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the height analyses in the UK Biobank, a much more homogeneously designed study. Our results show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population structure.

evolutionary biology↗