Sirui Zhou

Lady Davis Institute for Medical Research | LDI · Centre for Clinical Epidemiology (CCE)

Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to i...

The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated with many immune-mediated and infection-related diseases. Due to its highly polymorphic nature and complex linkage disequilibrium patterns, traditional genetic association studies of single nucleotide polymorphisms (SNPs) do not perform well in this region. Instead, the...

Metabolic processes can influence disease risk and provide therapeutic targets. By conducting genome-wide association studies of 1,091 blood metabolites and 309 metabolite ratios, we identified associations with 690 metabolites at 248 loci and associations with 143 metabolite ratios at 69 loci. Integrating metabolite-gene and gene expression inform...

Background Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Methods Using measurements of ~4000 plasma proteins in two cohorts of patients...

Objective Observational studies on cognition found that vitamin D supplementation is associated with improved cognition. Further, recent Mendelian randomization (MR) studies have shown that increased vitamin D levels, as measured by 25-hydroxyvitamin D [25(OH)D], may protect against Alzheimer’s disease. Thus, it is possible that 25OHD may protect a...

Hospital admission for COVID-19 remains common despite the successful development of vaccines and treatments. Thus, there is an ongoing need to identify targets for new COVID-19 therapies. Alternative splicing is an essential mechanism for generating functional diversity in protein isoforms and influences immune response to infection. However, the...

Introduction Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COV...

Background There is a pressing need of novel drug targets for psychiatric disorders. Circulating proteins are potential candidates because they are relatively easy to measure and modulate, and play important roles in signaling. Methods We performed two-sample Mendelian randomization (MR) analyses to estimate the associations between circulating pr...

Background: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. Materials and methods: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome...

Obesity is a major risk factor for COVID-19 severity; however, the underlying mechanism is not fully understood. Considering that obesity influences the human plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity. We first screened 4,907 plasma proteins to identify proteins influenced by b...

Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using longitudinally collected biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using longitudinal measurements of ∼4000 plasma proteins in two...

Despite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndro...

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse CO...

Calcium is widely used in conjunction with vitamin D to prevent osteoporosis. The use of calcium supplementation is also promoted for its potential benefits in lowering the risk for metabolic syndromes and cancers. However, the causal link between calcium and various health outcomes remains unclear. This review focuses on the evidence from twenty‐f...

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF. To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) appr...

Background Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mend...

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched popula...

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s...

Despite advances in COVID-19 management, it is unclear how to recognize patients who evolve towards death. This would allow for better risk stratification and targeting for early interventions. However, the explosive increase in correlates of COVID-19 severity complicates biomarker prioritisation. To identify early biological predictors of mortalit...

Background - The clinical implications of a polygenic risk score (PRS) for low-density lipoprotein cholesterol (LDL-C) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH). Methods - We developed the LDL-C PRS using LASSO regression in 377,286 white British participants from UK Biobank...

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched popula...

Background There has been uncertainty about the safety or benefit of angiotensin-converting enzyme (ACE) inhibitors during the Covid-19 pandemic. We used Mendelian randomization using genetic determinants of serum-ACE levels to test whether decreased ACE levels increase susceptibility to SARS-CoV-2 infection or Covid-19 severity, while reducing pot...

word count: 231) Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and also subject to confounding factors. To identify circulating proteins influencing COVID-19...

Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual’s fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%...

Introduction Increased vitamin D levels, as reflected by 25OHD measurements, has been proposed to protect against Covid-19 disease based on in-vitro , observational, and ecological studies. However, vitamin D levels are associated with many confounding variables and thus associations described to date may not be causal. Vitamin D MR studies have pr...

Vascular endothelial growth factor (VEGF) is important for bone formation and has been associated with osteoporosis in humans. Therefore, we conducted a two‐sample Mendelian randomization study to test whether genetically decreased circulating VEGF was associated with decreased bone mineral density (BMD) and increased risk of fracture. Summary stat...

The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genom...

Childhood‐onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal...

Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina...

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accomp...

Parkinson’s disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts includin...

Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and co...

Background: Inuit have lived for thousands of years in an extremely cold environment on a diet dominated by marine-derived fat. To investigate how this selective pressure has affected the genetic regulation of fatty acid metabolism, we assessed 233 serum metabolic phenotypes in a population-based sample of 1570 Greenlanders. Methods and results:...

Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used ex...

Objective: A common nonsense mutation in TBC1D4 was recently found to substantially increase the odds of type 2 diabetes in Greenlandic Inuit, leading to exclusively increased postprandial glucose. We investigated the frequency and effect of the TBC1D4 mutation on glucose metabolism and type 2 diabetes diagnosis among Canadian and Alaskan Inuit....

Background: The exact genetic causes within each of the known restless legs syndrome (RLS) loci are still unknown. Recently, it was suggested that an intronic protein tyrosine phosphatase, receptor type δ (PTPRD) single-nucleotide polymorphism (SNP) (reference SNP no. rs2381970) is associated with its expression, which may lead to RLS and other re...

Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing...

Background: Restless Legs Syndrome (RLS) is a common, age- and gender-related disorder. Although several genetic risk factors were identified, the actual genetic causes are unclear. Methods: Whole exome sequencing (WES) was performed in seven families with RLS, focusing on potential genetic causes around six known genetic loci; MEIS1, BTBD9, PTPRD,...

Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty aci...

Abstract Recurrent spontaneous abortion (RSA) is a health problem that affects nearly 1% of fertile couples. However, the underlying etiology and mechanism(s) remain elusive. The aim of this study was to investigate estrogen receptor (ESR) 1 gene polymorphisms for risk association of unexplained recurrent spontaneous abortion (URSA) in the Chinese...

We report here the description of a nonconsanguineous family with 2 affected individuals with a recessively inherited juvenile motor neuron disease. Exome sequencing of these 2 affected individuals led us to identify 2 compound heterozygous deletions leading to a frameshift and a premature stop codon in the SPG11 gene. One of these deletions, c.519...

Polycystic ovary syndrome (PCOS) is one of the common defects that cause ovary dysfunction and link to the aberrant process of folliculogenesis. Bone morphogenetic protein 15 (BMP15) is expressed in human oocytes and functions importantly to regulate early follicle growth and fertility. Previous studies have discovered several mutations in the scre...

Male sexual orientation has been proposed to have genetic components, but previously suggested candidate genes have all received negative results. The human sonic hedgehog (SHH) gene is located in the 7q36 region, which was linked to male sexual orientation in a previous genome-wide association study. SHH is known to play an important role in embry...

Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies. Al...

The WNT4 gene plays an important role in female sex determination and differentiation. It also contributes to maintaining of the ovaries and the survival of follicles. We sequenced the coding region and splice sites of WNT4 in 145 Han Chinese women with premature ovarian failure (POF) and 200 healthy controls. Only one novel variation, in Exon 2 (1...

We suspect that genes or loci that contribute to coronary artery disease (CAD) may also play a role in the pathogenesis of gout, since hyperuricaemia leads to gout, and serum uric acid (SUA) levels are potential risk factors for CAD. The single nucleotide polymorphism (SNP) rs1333049 (C/G) on chromosome 9p21 has been implicated in previous studies...

BACKGROUND Chemokine (C-X-C motif) ligand 12 (CXCL12/stromal cell-derived factor 1) has been suggested to play an essential role in primordial germ cell migration, colonization and survival, and in the primordial to primary follicle transition. This study was performed to investigate an association of polymorphisms in CXCL12 with the risk of premat...

To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family, molecular genetic investigation via haplotype analysis and direct sequencing were performed Sequencing of the CRYGD gene revealed a c.127T>C transition, which resulted in a substitution of a highly conserved tryptophan with arginine at...

Two common functional polymorphisms in the promoter region of TNF-α located at nucleotides -238 (rs361525) and -308 (rs1800629) have been reported to regulate the expression of tumour necrosis factor alpha (TNF-α) and to be associated with hepatitis B virus (HBV) infection related diseases. However, their frequencies and associations with outcomes...

The gene for growth differentiation factor 9 (GDF9) is expressed in human oocytes and has an important function in regulating early follicle growth and fertility. Polycystic ovary syndrome (PCOS) is one of the common defects that causes ovary dysfunction and is linked to aberrant processes in folliculogenesis. Previous studies have discovered sever...

TNF-alpha is a critical cytokine produced by Th1 cells while altered T helper 1 (Th1)-Th2 balance is found crucial for a successful pregnancy. A cohort of 132 Southern Chinese Han RSA patients and 152 controls constituted the subjects of this study. Two functional polymorphisms -308 and -238 of TNF-alpha were studied by association analysis. lack o...

Premature ovarian failure (POF) has recently been associated with mutations in Forkhead L2 (FOXL2) gene, which also being a candidate for blepharophimosis-ptosis-epicanthus inversus (BPES) syndrome. In the current study, we performed a screening analysis by polymerase chain reaction and direct sequencing in 118 patients, including one with BPES and...

GRB-associated binding protein 2 (GAB2) may function as a risk factor of Alzheimer disease (AD) by affecting hyperphosphorylation of tau, causing neurofibrillary tangles. There had been genomewide analysis discovering polymorphism rs2373115 correlated with AD and in this study we performed an association analysis on this polymorphism in 107:100 Mon...

This study screened FOXO3 coding regions for mutations in a sample of 114 Chinese women with premature ovarian failure and discovered six novel single-nucleotide variants: c.71C>A (p.Pro24His), c.140C>T (p.Pro47Leu), c.184G>A (p.Asp62Asn), c.1652C>T (p.Ser551Phe), c.1697C>G (p.Gly566Ala) and c.1185G>A (silent). The nonsynonymous single-nucleotide v...

PCOS is a complex multifactorial disorder involving a number of genetic and environmental factors. One of the genetic factors that has been associated with PCOS is Interleukin 1 beta (IL-1β), is an important inflammatory cytokine that plays a regulatory role in both the body's immune and the inflammatory responses. All these responses appear to be...

The G protein-coupled receptor gene GPR3 is expressed predominantly in oocytes, and functions in the early development of oocytes in the ovarian follicle. GPR3 is essential for meiotic arrest maintenance in mice, which makes it a candidate gene for premature ovarian failure (POF). The coding region of GPR3 was screened in 100 Chinese POF patients f...

To determine the relationship between apolipoprotein E (APOE) ε4 and sporadic Alzheimer's disease (SAD) in the Mongolian population in China, we examined 106 Mongolian SAD patients in China and 100 Mongolian healthy controls. All subjects were genotyped for APOE.The odds ratio (OR) for developing SAD was significantly increased in carriers of the A...

The epsilon4 version of the Apolipoprotein E gene has been proved to be a risk factor for the development of Alzheimer's disease (AD). Furthermore, another gene mitochondrial aldehyde dehydrogenase (ALDH2) has also been proposed to be potentially associated with AD, based on its possible relations toward acetaldehyde accumulation which further dama...

Polycystic ovary syndrome (PCOS) is a complex multi-factorial disorder involving a number of genetic and environmental factors. CYP1A1 (Cytochrome P450, family 1, subfamily A, polypeptide 1) gene, which belongs to Cytochrome P450 (CYP) super family, encodes a phase I cytochrome P450 enzyme, involved in the oxidative metabolism of estrogens. A recen...

Polycystic ovary syndrome (PCOS) is associated with the spontaneous development of an aberrant heterogeneous hormonal environment that thought to be related to multiple genetic or environmental factors remain undefined. Previous studies indicated that IL-1a gene C (-889) T, a polymorphism of the gene encoding a protein which involved in various imm...

Neuroinflammation and abnormal phosphorylation of TAU proteins have been implicated in the etiology of Alzheimer's disease (AD). Several studies have suggested the G-308A promoter polymorphism in one of the proinflammatory cytokine genes tumor necrosis factor-α (TNF-α) encoding TNF-α may be associated with AD pathogenesis. Association between the Q...

A functional polymorphism of mitochondrial aldehyde dehydrogenase gene (ALDH2 1/2 polymorphism) can influence the accumulation of acetaldehyde which may have a role in Alzheimer's disease (AD), and is widely prevalent among Mongoloids. Therefore ALDH2 1/2 polymorphism may represent a good candidate for genetic risk factors for AD, especially in Eas...

The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer’s disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk...