Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is par... more Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify four genomic loci with suggestive associations for SARS-CoV-2 susceptibility and nineteen for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. GWAS signals in eleven loci colocalize with eQTLs associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene) including lung, brain, heart, muscle, skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify ten GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome affecting gene expression levels in a wide variety of tissue types.
Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) hav... more Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ1-42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aβ1-42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1, APOE, and CLU (APOJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be high...
Additional file 5. 2% agarose gel electrophoresis of tetra primer ARMS-PCR test products for c.33... more Additional file 5. 2% agarose gel electrophoresis of tetra primer ARMS-PCR test products for c.332 T > C in the MAP3K19 gene. In this figure: well 1: 100 bp ladder, well 2: negative PCR test control (no template control; NTC), well 3: Homozygous for the normal allele, well 4: Heterozygous for the wild-type allele. The allele frequency was estimated at 0.031 for the c.332 T > C variant
Additional file 4. Sanger sequencing and conservational analysis for the candidate variants in MA... more Additional file 4. Sanger sequencing and conservational analysis for the candidate variants in MAP3K19 and XIRP2 genes. a) Chromatograms shed light on the cosegregation of c.332 T > C of MAP3K19 in the family members. b) Chromatograms showing nucleotide sequences of XIRP2 in the regions of c.9835 T > C. c) MetaDome shows that the c.332 T is located in a region with an average conservational profile in MAP3K19 protein. d) In this XIRP2 tolerance landscape, the region harboring the novel missense variant is partially tolerant in comparison with other parts in this protein. The affected region is located in a somehow variable region
Additional file 1. The karyotypes of the proband (a) and the male affected individual or III.4 (b... more Additional file 1. The karyotypes of the proband (a) and the male affected individual or III.4 (b). The karyotypes did not show any obvious chromosomal changes
Additional file 6. A simple and rapid PCR-RFLP assay was used to detect the c.9835 T > C varia... more Additional file 6. A simple and rapid PCR-RFLP assay was used to detect the c.9835 T > C variant in the XIRP2 gene. a) This schematic figure shows the generated fragments after digestion with the XapI restriction enzyme. The variant causes losing the restriction enzyme site. Agarose gel (2.0%) electrophoresis with ethidium bromide staining following the XapI digestion of the PCR products is shown. PCR-RFLP results in normal control showing 340, 249, and 130 bp (T/T: wild-type allele); after XapI digestion, a heterozygous sample will show four distinct bands including 470, 340, 249, and 130 bp. The homozygote reveals three distinct bands consisting of 470, 249, and 130 bp. b) PCR-RFLP assay was used on the samples in order to show the genotyping. In this figure, 1: heterozygote, 2: patient, 3–14, and 16–22 are wild-type alleles
Background The present study aimed to determine the underlying genetic factors causing the possib... more Background The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. Case presentation A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant—NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)—in the RAB3GAP1 gene was identified...
Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), a... more Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32–63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin fre...
SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID–19) has been responsible f... more SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID–19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID–19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The “Biobanque québécoise de la COVID-19” (BQC19) is a pan–provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative in...
INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early t... more INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.
ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral i... more ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflamma...
Open science can significantly influence the development and translational process of precision m... more Open science can significantly influence the development and translational process of precision medicine in Canada. Precision medicine presents a unique opportunity to improve disease prevention and healthcare, as well as to reduce health-related expenditures. However, the development of precision medicine also brings about economic challenges, such as costly development, high failure rates, and reduced market size in comparison with the traditional blockbuster drug development model. Open science, characterized by principles of open data sharing, fast dissemination of knowledge, cumulative research, and cooperation, presents a unique opportunity to address these economic challenges while also promoting the public good. The Centre of Genomics and Policy at McGill University organized a stakeholders’ workshop in Montreal in March 2018. The workshop entitled “Could Open be the Yellow Brick Road to Precision Medicine?” provided a forum for stakeholders to share experiences and identify...
In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease... more In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease (AD), a genome-wide association study was performed on a population isolate from Eastern Canada, referred to as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 is associated with higher AD risk and younger age at AD onset in APOE4- individuals. After surveying the region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when compared with age-matched controls. Using an independent cohort of cognitively normal individuals with a parental history of AD, we found that the rs10406151 C variant is significantly associated with lower visuospatial and constructional performances. The association of the rs10406151 C variant with AD risk appears to involve brain PPP2R1A gene expression alterations. However, the exact pathological pathway by which this variant modulates AD remains elusive.
Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is par... more Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify four genomic loci with suggestive associations for SARS-CoV-2 susceptibility and nineteen for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. GWAS signals in eleven loci colocalize with eQTLs associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene) including lung, brain, heart, muscle, skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify ten GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome affecting gene expression levels in a wide variety of tissue types.
Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) hav... more Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ1-42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aβ1-42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1, APOE, and CLU (APOJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be high...
Additional file 5. 2% agarose gel electrophoresis of tetra primer ARMS-PCR test products for c.33... more Additional file 5. 2% agarose gel electrophoresis of tetra primer ARMS-PCR test products for c.332 T > C in the MAP3K19 gene. In this figure: well 1: 100 bp ladder, well 2: negative PCR test control (no template control; NTC), well 3: Homozygous for the normal allele, well 4: Heterozygous for the wild-type allele. The allele frequency was estimated at 0.031 for the c.332 T > C variant
Additional file 4. Sanger sequencing and conservational analysis for the candidate variants in MA... more Additional file 4. Sanger sequencing and conservational analysis for the candidate variants in MAP3K19 and XIRP2 genes. a) Chromatograms shed light on the cosegregation of c.332 T > C of MAP3K19 in the family members. b) Chromatograms showing nucleotide sequences of XIRP2 in the regions of c.9835 T > C. c) MetaDome shows that the c.332 T is located in a region with an average conservational profile in MAP3K19 protein. d) In this XIRP2 tolerance landscape, the region harboring the novel missense variant is partially tolerant in comparison with other parts in this protein. The affected region is located in a somehow variable region
Additional file 1. The karyotypes of the proband (a) and the male affected individual or III.4 (b... more Additional file 1. The karyotypes of the proband (a) and the male affected individual or III.4 (b). The karyotypes did not show any obvious chromosomal changes
Additional file 6. A simple and rapid PCR-RFLP assay was used to detect the c.9835 T > C varia... more Additional file 6. A simple and rapid PCR-RFLP assay was used to detect the c.9835 T > C variant in the XIRP2 gene. a) This schematic figure shows the generated fragments after digestion with the XapI restriction enzyme. The variant causes losing the restriction enzyme site. Agarose gel (2.0%) electrophoresis with ethidium bromide staining following the XapI digestion of the PCR products is shown. PCR-RFLP results in normal control showing 340, 249, and 130 bp (T/T: wild-type allele); after XapI digestion, a heterozygous sample will show four distinct bands including 470, 340, 249, and 130 bp. The homozygote reveals three distinct bands consisting of 470, 249, and 130 bp. b) PCR-RFLP assay was used on the samples in order to show the genotyping. In this figure, 1: heterozygote, 2: patient, 3–14, and 16–22 are wild-type alleles
Background The present study aimed to determine the underlying genetic factors causing the possib... more Background The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. Case presentation A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant—NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)—in the RAB3GAP1 gene was identified...
Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), a... more Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32–63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin fre...
SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID–19) has been responsible f... more SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID–19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID–19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The “Biobanque québécoise de la COVID-19” (BQC19) is a pan–provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative in...
INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early t... more INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.
ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral i... more ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflamma...
Open science can significantly influence the development and translational process of precision m... more Open science can significantly influence the development and translational process of precision medicine in Canada. Precision medicine presents a unique opportunity to improve disease prevention and healthcare, as well as to reduce health-related expenditures. However, the development of precision medicine also brings about economic challenges, such as costly development, high failure rates, and reduced market size in comparison with the traditional blockbuster drug development model. Open science, characterized by principles of open data sharing, fast dissemination of knowledge, cumulative research, and cooperation, presents a unique opportunity to address these economic challenges while also promoting the public good. The Centre of Genomics and Policy at McGill University organized a stakeholders’ workshop in Montreal in March 2018. The workshop entitled “Could Open be the Yellow Brick Road to Precision Medicine?” provided a forum for stakeholders to share experiences and identify...
In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease... more In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease (AD), a genome-wide association study was performed on a population isolate from Eastern Canada, referred to as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 is associated with higher AD risk and younger age at AD onset in APOE4- individuals. After surveying the region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when compared with age-matched controls. Using an independent cohort of cognitively normal individuals with a parental history of AD, we found that the rs10406151 C variant is significantly associated with lower visuospatial and constructional performances. The association of the rs10406151 C variant with AD risk appears to involve brain PPP2R1A gene expression alterations. However, the exact pathological pathway by which this variant modulates AD remains elusive.
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