Sarah A Gagliano Taliun

Université de Montréal & Institut de Cardiologie de Montréal · Médecine & Neurosciences

Iron is an essential mineral that supports numerous biological functions. Studies have reported associations between iron dysregulation and certain cardiovascular and neurodegenerative diseases, but the direction of influence is not clear. Our goal was to use computational approaches to better understand the role of genetically predicted iron level...

MRI-detected white matter hyperintensities (WMH) are often recognized as markers of cerebrovascular abnormalities, an index of vascular brain injury, and are frequently present in individuals with Alzheimer disease (AD). Given the emerging bidirectional communication between the brain-body axis in both WMHs and AD, it is important to understand the...

Background Hematuria is an established sign of glomerular disease and can be associated with kidney failure, but there has been limited scientific study of this trait. Methods Here, we combined genetic data from the UK Biobank with predicted gene expression and splicing from GTEx kidney cortex samples (n = 65) in a transcriptome-wide association s...

Vascular cognitive impairment (VCI) is a heterogenous form of cognitive impairment that results from cerebrovascular disease. It is a result of both genetic and non‐genetic factors. Although much research has been conducted on the genetic contributors to other forms of cognitive impairment (e.g. Alzheimer's disease), knowledge is lacking on the gen...

It is established that there are sex differences in terms of prevalence, age of onset, clinical manifestations, and response to treatment for a variety of brain disorders, including neurodevelopmental, psychiatric, and neurodegenerative disorders. Cohorts of increasing sample sizes with diverse data types collected, including genetic, transcriptomi...

Parkinson's disease is a neurodegenerative disease characterised by a proteinopathy with marked astrogliosis. To investigate how a proteinopathy may induce a reactive astrocyte state, and the consequence of reactive astrocytic states on neurons, we generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-s...

Background Parental history of sporadic Alzheimer’s disease (AD) is considered a prime risk factor since at least the late 1980s. Routinely used clinical samples of at‐risk individuals (8‐16 subjects) may conceal weaker population‐based effects, especially those of paternal inheritance. We performed a phenome‐wide examination of the dissociable inf...

Our GWAS of hematuria in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Since clinical syndromes are often defined by combinations of traits, generating a combined phenotype can improve power to detect loci influencing multiple characteristics. Thus the composite trait of hematuria and album...

Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of stea...

Coronary artery disease (CAD) affects millions of individuals worldwide and results in a substantial burden to healthcare systems. Although it is established that CAD affects females differently than males, differences between the sexes are not routinely accounted for. Body mass index is a known risk factor for CAD. However, more accurate metrics o...

Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are devastating complex diseases resulting in physical and psychological burdens on patients and their families. There have been important efforts to understand their genetic basis leading to the identification of disease risk-associated loci involved in several molecular me...

Genetic correlation ( $$r_g$$ r g ) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, global $$r_g$$ r g analyses show minimal $$r_g$$ r g among neurodegenerative and neuropsychiatric diseases....

Background: Congenital heart disease (CHD) is highly heritable, but the power to identify inherited risk has been limited to analyses of common variants in small cohorts. Methods: We performed reimputation of 4 CHD cohorts (n=55 342) to the TOPMed reference panel (freeze 5), permitting meta-analysis of 14 784 017 variants including 6 035 962 rar...

Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants...

Polygenic risk scores (PRS) quantify the genetic liability to disease and are calculated using an individual's genotype profile and disease-specific genome-wide association study (GWAS) summary statistics. Type 1 (T1D) and type 2 (T2D) diabetes both are determined in part by genetic loci. Correctly differentiating between types of diabetes is cruci...

Linkage analysis, a class of methods for detecting co-segregation of genomic segments and traits in families, was used to map disease-causing genes for decades before genotyping arrays and dense SNP genotyping enabled genome-wide association studies in population samples. Population samples often contain related individuals, but the segregation of...

Alzheimer’s disease is marked by intracellular tau aggregates in the medial temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we examined codependent structural variations between the MTL’s most vulnerable structure, the hippocampus (HC), and the DN at subregion resolution in individuals with Alzheimer’s di...

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries⁵. Here we leveraged global genetic...

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD) and amyotrophic lateral sclerosis (ALS), are devastating complex diseases that result in a physical and psychological burden to patients and their families. There have been significant efforts to understand the genetic basis of neurode...

Parkinson's disease (PD) affects millions of individuals worldwide, and it is the second most common late-onset neurodegenerative disorder. There is no cure and current treatments only alleviate symptoms. Modifiable risk factors have been explored as possible options for decreasing risk or developing drug targets to treat PD, including low-density...

Understanding the genetic basis of human diseases and traits is dependent on the identification and accurate genotyping of genetic variants. Deep whole-genome sequencing (WGS), the gold standard technology for SNP and indel identification and genotyping, remains very expensive for most large studies. Here, we quantify the extent to which array geno...

Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of stea...

Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron-related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron-binding capacity) in the Trøndelag Health Study (HU...

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision...

Neurodegenerative diseases overlap neuropathologically and clinically, frequently manifesting with co-pathologies and comorbid symptoms that span multiple domains, including the neuropsychiatric. Genetically, shared risk loci have been identified across neurodegenerative diseases; however, global analyses of genetic correlation (r g ) show minimal...

While encephalisation has provided advantages to human evolution, it may have also predisposed us to neurological diseases as common neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease do not occur naturally in aged non-human primates. Thus, human lineage-specific genomic features may provide insights into brain-related diseases...

Background Humans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how commo...

Background and objectives: Glomerular hematuria has varied causes but can have a genetic basis, including Alport syndrome and IgA nephropathy. Design, setting, participants, & measurements: We used summary statistics to identify genetic variants associated with hematuria in White British UK Biobank participants. Individuals with glomerular hemat...

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 ×...

Alzheimer's disease and related dementias (ADRD) are marked by intracellular tau aggregates in the medial-temporal lobe (MTL) and extracellular amyloid aggregates in the default network (DN). Here, we sought to clarify ADRD-related co-dependencies between the MTL's most vulnerable structure, the hippocampus (HC), and the highly associative DN at a...

Iron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron binding capacity) in the Trøndelag Health Study (HU...

Biobanks housing genetic and phenotypic data for thousands of individuals introduce new opportunities and challenges for genetic association studies. Association testing across many phenotypes increases the multiple-testing burden and correlation between phenotypes makes appropriate multiple-testing correction uncertain. Moreover, analysis includin...

Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms unde...

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from two large population-based studies...

Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms unde...

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constr...

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenot...

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering v...

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the...

By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P < 2.14 x 10^-6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular...

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from the Trondelag Health Study and the...

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases...

With very large sample sizes, biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, region-based multiple-variant aggregate tests are commonly used to increase power for association tests. However, because of the substantial computational cost, existing region-based tests cannot analyze...

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constr...

Background: Although genome-wide association studies (GWAS) have made important strides in localizing genomic regions associated with blood pressure (BP) phenotypes, the causal mechanisms underlying the vast majority of identified signals remain to be elucidated. Whole genome sequencing (WGS) provides an opportunity for novel genomic discoveries an...

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling c...

Detecting and estimating DNA sample contamination are important steps to ensure high-quality genotype calls and reliable downstream analysis. Existing methods rely on population allele frequency information for accurate estimation of contamination rates. Correctly specifying population allele frequencies for each individual in early stage of sequen...

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regressi...

The past decade has seen a surge in the number of disease/trait-associated variants, largely because of the union of studies to share genetic data and the availability of electronic health records from large cohorts for research use. Variant discovery for neurological and neuropsychiatric genome-wide association studies, including schizophrenia, Pa...

Some scientists should reconsider their position on teaching responsibilities, says Sarah A. Gagliano Taliun. Some scientists should reconsider their position on teaching responsibilities, says Sarah A. Gagliano Taliun. Tutor is teaching a group of diverse science students practical skills.

The power of genetic association analyses can be increased by jointly meta‐analyzing multiple correlated phenotypes. Here, we develop a meta‐analysis framework, Meta‐MultiSKAT, that uses summary statistics to test for association between multiple continuous phenotypes and variants in a region of interest. Our approach models the heterogeneity of ef...

Polygenic risk scores (PRS) are designed to serve as single summary measures that are easy to construct, condensing information from a large number of genetic variants associated with a disease. They have been used for stratification and prediction of disease risk. The primary focus of this paper is to demonstrate how we can combine PRS and electro...

Introduction: There is observational evidence that low circulating levels of vitamin B12 are associated with an increased risk of Alzheimer's disease. Methods: We used a two-sample summary-statistics-based Mendelian randomization design to assess the relationship of genetic factors contributing to vitamin B12 with late-onset Alzheimer's disease...

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with various human phenotypes and many of these loci are thought to act at a molecular level by regulating gene expression. Detection of allele specific expression (ASE), namely preferential usage of an allele at a transcribed locus, is an increasingly i...

Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally. Lowering circulating lipids is an important treatment strategy to reduce risk. However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders. To identify...

The power of genetic association analyses can be increased by jointly meta-analyzing multiple correlated phenotypes. Here, we develop a meta-analysis framework, Meta-MultiSKAT, that uses summary statistics to test for association between multiple continuous phenotypes and variants in a region of interest. Our approach models the heterogeneity of ef...

Genome-wide association studies have generated an increasing number of common genetic variants that affect neurological and psychiatric disease risk. Given that many causal variants are likely to operate by regulating gene expression, an improved understanding of the genetic control of gene expression in human brain is vital. However, the difficult...

With very large sample sizes, population-based cohorts and biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, gene or region-based multiple variant aggregate tests are commonly used to increase association test power. However, due to the substantial computation cost, existing region-...

paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic...

Despite the wealth of genomic and transcriptomic data in Parkinson’s disease (PD), the initial molecular events are unknown. Using LD score regression analysis, we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected br...

In the original publication of this article, the author Magarida Rodrigues was written incorrectly. The correct spelling should have been Margarida Rodrigues. Also the centrifuge speed used to remove fibrillar pellets from the aggregation reaction was written incorrectly as 14.2 rpm and should have been 14,200 rpm. The original article has now been...

It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant single‐nucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up...