Johanna Kuusisto

• Professor; cardiologist, internist
• Professor at University of Eastern Finland

Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL g...

Aims To investigate a comprehensive panel of biomarkers and risk of aortic stenosis (AS) in a prospective population-based study. Methods Anthropometric, metabolic, and inflammatory biomarkers were measured in the Metabolic Syndrome in the Men Study of 10,144 Finnish men without AS at baseline. Cases of AS were identified from the medical records....

Background Patients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis...

Central obesity (CO), characterized by an increased waist circumference increases the risk of cardiovascular disease (CVD) and morbidity, yet the underlying mechanisms are not fully understood. CO is often associated with general obesity, hypertension, and abnormal glucose tolerance, confounding the independent contribution of CO to CVD. We investi...

Alzheimer's disease (AD) patients often exhibit cerebral amyloid angiopathy (CAA), i.e beta-amyloid (Abeta) accumulation within cerebral blood vessels causing cerebrovascular dysfunction. Pericytes wrap around vascular capillaries, thus regulating cerebral blood flow, angiogenesis, and vessel stability. Vascular dysfunction can promote the developm...

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples w...

2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We fou...

Background/Introduction Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the α- galactosidase A gene (GLA) leading to lack of an active GLA enzyme and accumulation of glycosphingolipids in different organs, including heart. Because of X-linked inheritance, the phenotype is usually more severe in males than in females. Purp...

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilist...

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline r...

Introduction: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E Ɛ4 genotype. Methods: We...

Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise ra...

Systematic insight into cellular dysfunction can improve understanding of disease etiology, risk assessment, and patient stratification. We present a multiparametric high-content imaging platform enabling quantification of low-density lipoprotein (LDL) uptake and lipid storage in cytoplasmic droplets of primary leukocyte subpopulations. We validate...

Alternate splicing events can create isoforms that alter gene function, and genetic variants associated with alternate gene isoforms may reveal molecular mechanisms of disease. We used subcutaneous adipose tissue of 426 Finnish men from the METSIM study and identified splice junction quantitative trait loci (sQTLs) for 6,077 splice junctions (FDR <...

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,...

Few studies have explored the impact of rare variants (minor allele frequency, MAF<1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise...

Background Familial hypercholesterolemia (FH) is the most frequent monogenic disease with an estimated prevalence of 1:250. The prevalence of different variants varies widely between the populations. According to previous studies, the prevalence of heterozygous FH in Finland has been reported to be 1:400–650, seven Finnish LDLR founder mutations ha...

Background and aims To investigate the significance of nine amino acids as risk factors for incident cardiovascular disease events in 9,584 Finnish men. Materials and Methods A total of 9,584 men (age 57.4±7.0 years, body mass index 27.2±4.2 kg/m 2) from the METSIM study without cardiovascular disease and type 1 diabetes at baseline were included...

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult indi...

Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation...

Differences in cellular lipid metabolism may underlie large interindividual variability in lipid disorders such as hypercholesterolemia. Here, we established a multi-parametric imaging platform enabling the quantification of lipid uptake and storage in cytoplasmic droplets of leukocyte populations from 2-4 ml of peripheral blood. We define a new qu...

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confiden...

The incidence of type 2 diabetes (T2D) has been increasing globally, and a growing body of evidence links type 2 diabetes with altered microbiota composition. Type 2 diabetes is preceded by a long prediabetic state characterized by changes in various metabolic parameters. We tested whether the gut microbiome could have predictive potential for T2D...

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women...

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency<1%) predicted damaging coding variation using sequence data from >170,000 individuals from multiple ancestries: 97,493 E...

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confiden...

Aims There are only a few studies on novel biomarkers for incident heart failure (HF). We investigated the association of multiple circulating biomarkers with incident HF in a large prospective population‐based study. Methods and results Conventional risk factors and inflammatory biomarkers were measured, and systemic metabolic measures determined...

Background Subjects with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) have left ventricular hypertrophy (LVH). It is a common clinical problem to distinguish HCM from HHD. Septal convexity (SC) into the left ventricle is increased in subjects with hypertrophic cardiomyopathy (HCM)-causing mutations with and without LVH. P...

Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell type composition. Here, we studied MT-CN variation in blood-d...

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult...

The incidence of type 2 diabetes (T2D) has been increasing globally and a growing body of evidence links type 2 diabetes with altered microbiota composition. Type 2 diabetes is preceded by a long pre-diabetic state characterized by changes in various metabolic parameters. We tested whether the gut microbiome could have predictive potential for T2D...

Background: Left ventricle rotation and torsion are fundamental components of myocardial function, and several software packages have been developed for analysis of these components. The purpose of this study was to compare the suitability of two software packages with different technical principles for analysis of rotation and torsion of the left...

Objective To investigate whether the Ala143Thr variant of the α-galactosidase A gene (A143T/ GLA ), with conflicting interpretations of pathogenicity, is associated with Fabry cardiomyopathy. Methods The index patient, a woman in her 60s with cardiomyopathy, was screened for variants in 59 cardiomyopathy-related genes. A143T/ GLA , the only rare v...

Background Left ventricle rotation and torsion are fundamental components of myocardial function, several software have been developed for the analysis of these components. Purpose of the study was to compare the suitability of two such software with different technical principles in analyzing rotation and torsion of the left ventricle during syst...

Background: Left ventricle rotation and torsion are fundamental components of myocardial function, and several software packages have been developed for analysis of these components. The purpose of this study was to compare the suitability of two software packages with different technical principles for analysis of rotation and torsion of the left...

Integration of genome-wide association study (GWAS) signals with expression quantitative trait loci (eQTL) studies enables identification of candidate genes. However, evaluating whether nearby signals may share causal variants, termed colocalization, is affected by the presence of allelic heterogeneity, different variants at the same locus impactin...

BACKROUND Recent studies show that hypertension predicts aortic stenosis (AS). Other predictors of AS are not established. Purpose To investigate a large panel of biomarkers as predictors of AS in the population-based METSIM cohort. Methods Anthropometric, metabolic and inflammatory biomarkers were measured at baseline in the cohort of 10,197 Fin...

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d⁻¹) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genom...

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identi...

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequenc...

This manuscript has not been published before and is not currently being considered for publication elsewhere. Increased septal convexity of left ventricle has been described in subjects with hypertrophic cardiomyopathy (HCM) -causing mutations without left ventricular hypertrophy (LVH). Our objective was to study septal convexity by cardiac magnet...

Several amino acids (AAs) have been shown to be associated with insulin resistance and increased risk of type 2 diabetes, but no previous studies have investigated the association of AAs with insulin secretion in a longitudinal setting. Our study included 5,181 participants of the cross-sectional METabolic Syndrome In Men (METSIM) study having meta...

Aims Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy‐associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most m...

Data S1. Supporting information.

Table S1. List of the 59 genes included in the FinHCM Genetic Study screening.

Table S2. Clinical characteristics of the FinHCM Genetic Study (n=382).

Table S3. A list of all 382 patients with HCM included in the FinHCM Genetic Study, and the rare variants (GMAF > 1 %) detected in each patient.

Table S4. Variants with conflicting evidence favouring pathogenicity, or with uncertain significance found in the FinHCM Genetic Study (n=382).

Table S6. New events in the FinHCM Outcome Study (n=482).

Table S5. Baseline characteristics of the patients of the FinHCM Outcome Study (n=482).

Table S8. Univariate and multivariate predictors (Cox regression) of combined HCM‐related mortality and life‐threatening HCM events in the FinHCM Outcome Study.

Table S7. HCM‐related deaths and their circumstances in the FinHCM Outcome Study.

Type 2 Diabetes Mellitus (T2DM) is the most prevalent form of diabetes in the USA, thus, the identification of biomarkers that could be used to predict the progression from prediabetes to T2DM would be greatly beneficial. Recently, circulating RNA including microRNAs (miRNAs) present in various body fluids have emerged as potential biomarkers for v...

Enzyme replacement therapy (ERT) has stabilized renal function but its effect on proteinuria is inconsistent. Also nephroprotective renin-angiotensin-aldosterone system (RAAS) inhibition is warranted. We calculated eGFR using CKD-EPI formula and albuminuria using urine albumin/creatinine ratio (ACR) once a year in 12 Fabry patients with ERT for 10...

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of di...

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) en...

The rs780094 single nucleotide polymorphism (SNP; C/T) of glucokinase regulatory protein gene (GCKR) is a regulatory genetic variant that has been associated with lactate levels in the fasting state. However, the association of this locus with lactate during hyperglycemia, and the mechanisms underlying these associations remain unknown. We investig...

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and invest...

Objective Apolipoprotein E (APOE) ε4 allele is a well‐established risk factor in Alzheimer's disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation‐related parameters in population‐based cohorts. Methods Association of cardiovascular, metabolic, and inflammation‐related parameters with the A...

Table S1. Cardiovascular health and metabolic parameters studied in METSIM cohort at the baseline.

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage....

Background Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. Methods HCM patients with either the MYBPC3‐Q1061X or TPM1‐D175N mutation (n = 46) and con...

Objectives: The sensitivity and specificity of the conventional 12-lead ECG to identify carriers of hypertrophic cardiomyopathy (HCM) - causing mutations without left ventricular hypertrophy (LVH) has been limited. We assessed the ability of novel electrocardiographic parameters to improve the detection of HCM mutation carriers. Methods: We stud...

Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of ef...

Background: Elevated levels of adiponectin, an adipose-tissue derived hormone, are associated with a decreased risk for development of obesity, cardiovascular disease, and type 2 diabetes. We sought to fine-map and characterize loci from an adiponectin genome-wide association study (GWAS) to better understand the genes, variants, and mechanisms tha...

Most epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. To determine if natural variation in DNA methylation was associated with metabol...

Most epigenome-wide association studies to date have been conducted in blood. However, metabolic syndrome is mediated by a dysregulation of adiposity and therefore it is critical to study adipose tissue in order to understand the effects of this syndrome on epigenomes. To determine if natural variation in DNA methylation was associated with metabol...

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (a...

This corrects the article DOI: 10.1038/sdata.2017.179.

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]<5%), identified 243 genome-wide significant loci ( p <5×10 ⁻⁸ ; MAF 0.02%-50%; odds ratio [OR] 1.04-8...

Background: There is a need for early markers to track and predict the development of type 2 diabetes mellitus (T2DM) from the state of normal glucose tolerance through prediabetes. In this study we tested whether the plasma molecular lipidome has biomarker potential to predicting the onset of T2DM. Methods: We applied global lipidomic profiling...

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-freque...

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-freque...

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted...