Lucija Klarić

Genos Ltd. · Glycobiology Laboratory

The benefits of returning clinically actionable genetic results to participants in research cohorts are accruing, yet such a genome-first approach is challenging. Here, we describe the return of such results in two founder populations from Scotland. Between 2005 and 2015, we recruited >4,000 adults with grandparents from Orkney and Shetland into th...

For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK population...

For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK population...

Coagulation Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with cir...

Understanding the genomic basis of human proteomic variability provides powerful tools to probe potential causal relationships of proteins and disease risk, and thus to prioritise candidate drug targets. Here, we investigated 6432 plasma proteins (1533 previously unstudied in large-scale proteomic GWAS) using the SomaLogic (v4.1) aptamer-based tech...

Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a...

Biological age captures physiological deterioration better than chronological age and is amenable to interventions. Blood-based biomarkers have been identified as suitable candidates for biological age estimation. This study aims to improve biological age estimation using machine learning models and a feature-set of 60 circulating biomarkers availa...

Background Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. Methods We conducted a meta-analysis on genome-wide assoc...

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory t...

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory t...

Glycans are an essential structural component of Immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a...

Human plasma transferrin (Tf) N-glycosylation has been mostly studied as a marker for congenital disorders of glycosylation, alcohol abuse, and hepatocellular carcinoma. However, inter-individual variability of Tf N-glycosylation is not known, mainly due to technical limitations of Tf isolation in large-scale studies. Here, we present a highly spec...

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of...

Aims/hypothesis We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes...

Biological Age (BA) captures physiological deterioration better than chronological age and is amenable to interventions. Blood-based biomarkers have been identified as suitable candidates for BA estimation. This study aims to improve BA estimation using machine learning models and a feature-set of 60 circulating biomarkers available from the UK Bio...

Background: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. Methods: We conducted a meta-analysis on genome-wide asso...

Obesity remains an unmet global health burden. Detrimental anatomical distribution of body fat is a major driver of obesity-mediated mortality risk and is demonstrably heritable. However, our understanding of the full genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. To address this, we impute whole-b...

It is often difficult to be certain which genes underlie the effects seen in association studies. However, variants that disrupt the protein, such as predicted loss of function (pLoF) and missense variants, provide a shortcut to identify genes with a clear biological link to the phenotype of interest. Glycosylation is one of the most common post-tr...

Bile acids are essential for food digestion and nutrient absorption, but also act as signalling molecules involved in hepatobiliary diseases, gastrointestinal disorders and carcinogenesis. While many studies have focused on the genetic determinants of blood metabolites, research focusing specifically on genetic regulation of bile acids in the gener...

Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum p...

Introduction: Cardiovascular disease (CVD) is the leading cause of death for people with type 2 diabetes (T2D). The predictive performance of existing CVD risk scores in T2D populations is suboptimal. Metabolomics is a promising method of identifying novel biomarkers which might improve risk prediction. We aimed to identify a group of metabolites a...

The BRCA1 pathogenic missense variant c.5207T>C; p.Val1736Ala (V1736A) was multiply ascertained in the clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isl...

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datase...

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, play...

Objective Deep sequencing offers unparalleled access to rare variants in human populations. Understanding their role in disease is a priority, yet prohibitive sequencing costs mean that many cohorts lack the sample size to discover these effects on their own. Meta-analysis of individual variant scores allows the combination of rare variants across...

Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2–4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population c...

Pulmonary inflammation drives critical illness in Covid-19, creating a clinically homogeneous extreme phenotype, which we have previously shown to be highly efficient for discovery of genetic associations. Despite the advanced stage of illness, we have found that immunomodulatory therapies have strong beneficial effects in this group. Further genet...

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to compare fifteen omics ageing...

Changes in the N-glycosylation of immunoglobulin G (IgG) are often observed in pathological states, such as autoimmune, inflammatory, neurodegenerative, cardiovascular diseases and some types of cancer. However, in most cases it is not clear if the disease onset causes these changes, or if the changes in IgG N-glycosylation are among the risk facto...

Defining the genetic components that control glycosylation of the human immunoglobulin G (IgG) is an ongoing effort, which has so far been addressed by means of heritability, linkage and genome-wide association studies (GWAS). Unlike the synthesis of proteins, N-glycosylation biosynthesis is not a template-driven process, but rather a complex proce...

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care or hospitalisation following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compa...

We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL ov...

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tes...

Post-translational modifications (PTMs) diversify protein functions and dynamically coordinate their signalling networks, influencing most aspects of cell physiology. Nevertheless, their genetic regulation or influence on complex traits is not fully understood. Here, we compare for the first time the genetic regulation of the same PTM of two protei...

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quant...

The N-glycosylation of immunoglobulin G affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regu...

Estimates from genome-wide association studies (GWAS) represent a combination of the effect of inherited genetic variation (direct effects), demography (population stratification, assortative mating) and genetic nurture from relatives (indirect genetic effects). GWAS using family-based designs can control for demography and indirect genetic effects...

Host-mediated lung inflammation is present,¹ and drives mortality,² in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.³ Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2...

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to create eleven omics ageing c...

Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS), with unresolved aetiology. Previous studies have implicated N-glycosylation, a highly regulated enzymatic attachment of complex sugars to targeted proteins, in MS pathogenesis. We investigated individual variation in N-glycosylation of the tot...

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs[PMID: 32526193] and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.[PMID: 32678530] Since susceptibility to life-threatening infections and im...

Genome-wide association studies have led to a significant progress in identification of genomic loci affecting coronary artery disease (CAD) risk. However, revealing the causal genes responsible for the observed associations is challenging. In the present study, we aimed to prioritize CAD-relevant genes based on cumulative evidence from the publish...

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tes...

Rapid progress in high-throughput glycomics analysis enables the researchers to conduct large sample studies. Typically, the between-subject differences in total abundance of raw glycomics data are very large, and it is necessary to reduce the differences, making measurements comparable across samples. Essentially there are two ways to approach thi...

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation ( N = 8090) an...

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole geno...

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole geno...

Type 1 diabetes (T1D) is an autoimmune disease with an unknown cause. It is characterised by the destruction of pancreatic insulin producing beta cells. Glycosylation is a ubiquitous protein modification, but studies of glycosylation changes in T1D are scarce. We studied plasma samples of 1105 children and adolescents (0-18 years), collected within...

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and disease...

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome...

Adult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males...

Glycosylation is a common post-translational modification of proteins. It is known, that glycans are directly involved in the pathophysiology of every major disease. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here, we report a genome-wide association study...

Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody’s effector function, is essential for prompting a proper immune response. This study focuses on the...

Mirrored Manhattan plot of all suggestive (p < 5 × 10−8) and replicated (p < 2.33 × 10−6) SNPs with their minimal p-values for any association.

Enzymatic pathway steps in IgG glycosylation. (Colors indicate the enzymes responsible for the attachment of monosaccharides.) (A) Known enzymatic pathway steps in IgG glycosylation (the glycosylation pathways are assumed to be the same for all IgG subclasses). (B) Known and suggested (dashed) one-step enzymatic pathway steps in IgG glycosylation (...

(A–G) Regional association plots for SNPs and their lowest p-values for any association for each linkage disequilibrium (LD)-block (only if LD information was available). (A) RUNX3 (chr.1), LD-block 1, [(B), i–iv] ST6GAL1 (chr.3), LD-block 1–LD-block 4, (C) IKZF1 (chr.7), LD-block 1, [(D) i, ii] B4GALT1 (chr.9), LD-block 1, and LD-block 2, [(E), i,...

Description of immunoglobulin G (IgG) glycopeptide traits.

Network of significantly different associated IgG glycopeptide traits and SNPs summarized by linkage disequilibrium-blocks IgG glycan traits (circles) for different subclass comparisons (red: IgG1 vs. IgG4; light green: IgG1 vs. IgG2; blue: IgG2 vs. IgG4; purple: glycan proportions for IgG4; and green: glycan proportions for IgG2) and their associa...

(A) QQ-Plot (−log10(p-values)) for comparison of results from initial glycopeptide traits and from between-subclass ratios and glycan proportions (results are obtained from the discovery cohort only). (B) QQ-Plot (−log10(p-values)) for comparison of results from all known pathway steps and additionally suggested pathway steps (known relations inclu...

List of association in KORA F4 to SNPs excluded for the replication due to unavailability in Leiden Longevity Study.

Complete list of results for subclass comparisons of immunoglobulin G (IgG) glycopeptide traits.

Overview of results from subclass comparisons of immunoglobulin G (IgG) glycopeptide traits.

(A–G) Representation of the linkage disequilibrium-blocks summarizing the replicated SNPs for each gene region. (A) RUNX3 (chr.1), (B) ST6GAL1 (chr.3), (C) IKZF1 (chr.7), (D) B4GALT1 (chr.9), (E) FUT8 (chr.14), (F) SMARCB1-DERL3 (chr.22), and (G) MGAT3 (chr.22).

List of all replicated associations.

Comparison of ultra-performance liquid chromatography (UPLC)-measured and LC/MS-measured immunoglobulin G (IgG) glycan traits [adapted from Huffman et al. (24)].

Summary of replicated association and comparison to study by Lauc et al. (21).

Study characteristics of the discovery cohort KORA.

Explained variance of the immunoglobulin G (IgG) glycopeptide traits by the single SNPs in KORA.

Confirmation of loci reported in Lauc et al. (21).

List of replicated phenotypic traits for each gene region.

Replicated association and comparison to the study by Lauc et al. (21).

Results from joint linear models for replicated SNPs on chromosome 1.

Correction to: Nature Communications (2017) 8:1231. doi:10.1038/s41467-017-01525-0.

Joint modeling of a number of phenotypes using multivariate methods has often been neglected in genome-wide association studies and if used, replication has not been sought. Modern omics technologies allow characterization of functional phenomena using a large number of related phenotype measures, which can benefit from such joint analysis. Here, w...