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Kári Stéfansson

Kári Stéfansson

Preventive Cardiology

deCODE Genetics (Iceland)

About

Kári Stéfansson works in Preventive Cardiology affiliated with deCODE Genetics (Iceland).

Kári Stefánsson is an Icelandic neurologist and geneticist who founded deCODE genetics in Reykjavík. He served as CEO of deCODE genetics until 2025 and is Professor Emeritus at the University of Iceland. He has affiliations with the Broad Institute and his research encompasses genetic factors in cardiovascular diseases.

Research focus

Genetics of coronary artery diseaseGenetic variants for atrial fibrillationGenetic risk factors for peripheral artery diseaseGenetics of aortic and intracranial aneurysmsVariants associated with sick sinus syndrome

Impact

1,148 pubs · 207,075 cites · h-index 218

Training

MD
University of Iceland
1976
Dr. med.
University of Iceland
1986

Affiliations

Work Experience

Professor Emeritus

University of Iceland · 2010 - Present

Founder and CEO

deCODE Genetics · 1996 - 2025

Professor of Neurology, Neuropathology, and Neuroscience

Harvard University · 1993 - 1997

Division Chief of Neuropathology

Beth Israel Hospital · 1997

Faculty Member

University of Chicago · 1983 - Present

Publications

Deepak Voora

Instructor of Medicine, Division of Cardiology, Duke University · Duke University

3w

The main conclusion to draw from this work is that Lp(a) is probably a strong causal factor in not only CAD, but also the development of atherosclerosis in other arterial trees. Although there is no evidence from this study that Lp(a) levels contribute to venous thrombosis, the investigators do not exclude a role for Lp(a) in arterial thrombosis.

Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism

Journal of the American College of CardiologyHelgadóttir et al.Aug 2012

case-control · n=78,000

JUN 2022GhouseEuropean Heart Journal

Variant at 20q13.3 linked to ~21% higher ACE-inhibitor discontinuation, primarily driven by cough.

A genome-wide association study identified seven genetic loci associated with ACEi discontinuation, which were also strongly linked to ACEi-associated cough, providing new insights into the genetic basis of this common adverse drug reaction.

Jun 2022Open Access

Level 4: Case-Control

GhouseEuropean Heart Journal

Variant at 20q13.3 linked to ~21% higher ACE-inhibitor discontinuation, primarily driven by cough.

Implication

A genome-wide association study identified seven genetic loci associated with ACEi discontinuation, which were also strongly linked to ACEi-associated cough, providing new insights into the genetic basis of this common adverse drug reaction.

case-control · n=47,9012 mentionsTrending on X

JUL 9TraganteHypertension

ENPEP stop-gain variant linked to ~28% higher resistant hypertension risk via hyperaldosteronism.

May support aldosterone antagonist preference in resistant hypertension; leaves open prospective validation of genetic hyperaldosteronism causality.

Graphical abstract

17w agoOpen Access

Trending on X

Level 4: Case-Control

TraganteHypertension

ENPEP stop-gain variant linked to ~28% higher resistant hypertension risk via hyperaldosteronism.

Implication

May support aldosterone antagonist preference in resistant hypertension; leaves open prospective validation of genetic hyperaldosteronism causality.

Graphical abstract

Meta-Analysis

MAY 25TyrmiNature Communications

Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy

23w agoOpen Access

TyrmiNature Communications

Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy

meta-analysis · n=1,255,2763 mentionsTrending on XEuropean Heart Journal Highlight

FEB 2023AegisdottirEuropean Heart Journal

GWAS meta-analysis identifies 18 genetic variants linked to syncope, pointing to neural regulatory processes.

Syncope has a distinct genetic architecture implicating neural regulatory processes and shares a genetic background with poor cardiovascular health.

Feb 2023Open Access

Trending on XEuropean Heart Journal Highlight

Level 1: Meta-Analysis

AegisdottirEuropean Heart Journal

GWAS meta-analysis identifies 18 genetic variants linked to syncope, pointing to neural regulatory processes.

Implication

Syncope has a distinct genetic architecture implicating neural regulatory processes and shares a genetic background with poor cardiovascular health.

case-control · n=339,25210 mentionsEuropean Heart Journal Highlight

OCT 2016GuðbjartssonEuropean Heart Journal

Homozygous MYL4 loss-of-function mutation causes early-onset familial AF with complete penetrance.

May warrant MYL4 testing in early-onset familial AF; leaves open broader risk, penetrance, and therapeutic translation.

Oct 2016Open Access

European Heart Journal Highlight

Level 4: Case-Control

GuðbjartssonEuropean Heart Journal

Homozygous MYL4 loss-of-function mutation causes early-onset familial AF with complete penetrance.

Implication

May warrant MYL4 testing in early-onset familial AF; leaves open broader risk, penetrance, and therapeutic translation.

meta-analysis · n=744,695European Heart Journal Highlight

APR 2023ChenEuropean Heart Journal

A genetic risk score was significantly associated with aortic stenosis (OR per standard deviation 1.31; 95% CI 1.26-1.35; P=2.7×10-51), implicating dyslipidemia, inflammation, and adiposity.

This large-scale genomic study identifies novel genetic loci for aortic stenosis and provides Mendelian randomization evidence that apolipoprotein B-containing lipoproteins, Lp(a), and BMI are causally related to its development.

Graphical abstract

Apr 2023Open Access

European Heart Journal Highlight

Level 1: Meta-Analysis

ChenEuropean Heart Journal

A genetic risk score was significantly associated with aortic stenosis (OR per standard deviation 1.31; 95% CI 1.26-1.35; P=2.7×10-51), implicating dyslipidemia, inflammation, and adiposity.

Implication

This large-scale genomic study identifies novel genetic loci for aortic stenosis and provides Mendelian randomization evidence that apolipoprotein B-containing lipoproteins, Lp(a), and BMI are causally related to its development.

Graphical abstract

meta-analysis · n=2,853,408

DEC 2025SmallNature Genetics

Discovered 241 autosomal independent risk loci and 3 X chromosome risk loci for aortic stenosis, and demonstrated that silencing CMKLR1 and LTBP4 decreases mineralization in human valvular interstitial cells.

Identifies extensive genetic risk loci for aortic stenosis; leaves open translation to clinical risk prediction or therapies.

Figure from the paper

45w agoOpen Access

Level 1: Meta-Analysis

SmallNature Genetics

Discovered 241 autosomal independent risk loci and 3 X chromosome risk loci for aortic stenosis, and demonstrated that silencing CMKLR1 and LTBP4 decreases mineralization in human valvular interstitial cells.

Implication

Identifies extensive genetic risk loci for aortic stenosis; leaves open translation to clinical risk prediction or therapies.

Figure from the paper

Original Research

NOV 2025GretarsdottirHuman Molecular Genetics

Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition

Observational analysis shows no significant impact of sclerostin inhibition on cardiovascular disease risk in individuals, suggesting alternative approaches may be necessary.

50w ago

GretarsdottirHuman Molecular Genetics

Observational and Mendelian randomization studies of plasma sclerostin levels do not provide evidence of cardiovascular adverse effects of sclerostin inhibition

Implication

Observational analysis shows no significant impact of sclerostin inhibition on cardiovascular disease risk in individuals, suggesting alternative approaches may be necessary.

#cardiovascular-diseases#mendelian-randomization#sclerostin

GWAS

NOV 2025ThorlaciusNature Genetics

African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies. Whole-genome sequencing identifies a rare missense variant in IKBKB associated with high risk of cutaneous and systemic lupus erythematosus among people with African ancestry.

50w agoOpen Access

Level 4: GWAS

ThorlaciusNature Genetics

African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk

Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies. Whole-genome sequencing identifies a rare missense variant in IKBKB associated with high risk of cutaneous and systemic lupus erythematosus among people with African ancestry.

Case-Control Study

OCT 2025KogelmanBMC Medicine

The burden of endometriosis on quality of life in Danish women: an analysis of the Danish Blood Donor Study

Case-control study reveals increased gastrointestinal, sleep, and conception issues in women with endometriosis, highlighting complex clinical and genetic overlaps.

Oct 2025Open Access

Level 4: Case-Control

KogelmanBMC Medicine

The burden of endometriosis on quality of life in Danish women: an analysis of the Danish Blood Donor Study

Implication

Case-control study reveals increased gastrointestinal, sleep, and conception issues in women with endometriosis, highlighting complex clinical and genetic overlaps.

Original Research

OCT 2025ArnadottirObstetrical & Gynecological Survey

Sequence Diversity Lost in Early Pregnancy

Oct 2025

ArnadottirObstetrical & Gynecological Survey

Sequence Diversity Lost in Early Pregnancy

Original Research

OCT 2025LeffersTranslational research

Autoantibody-defined subsets of patients with systemic lupus erythematosus associate with clinical manifestations, NCF2, and HLA DR3-DQ2 genotypes

INTRODUCTION: Understanding the associations between genetic markers, serological subsets and clinical manifestations in patients with Systemic lupus erythematosus (SLE) may elucidate disease mechanisms and inform personalised treatment strategies. This study aimed to classify SLE patients into distinct subsets based on autoantibody profiles and to examine associations with clinical and genetic characteristics, focusing on key risk loci. METHODS: A cohort of 846 SLE patients from the Danish SLE Gene-Environment Interaction study (SLE-GEIST) was analysed. Patients were grouped by cluster analysis of cumulative history of autoantibody positivity, and genotyped for known risk alleles, including HLA and non-HLA variants. Multinomial, multivariable logistic regression models were employed to identify associations between autoantibody subsets, clinical manifestations, and genetic markers. RESULTS: Six serological subsets with distinct characteristics were identified. The NCF2 variant was significantly associated with the subset characterised by antiphospholipid antibodies, showing an odds ratio (OR) of 2.42 (95% confidence interval [CI] 1.24-4.74) for co-positivity of anti-cardiolipin IgG and anti-beta2-glycoprotein IgG. This subset also demonstrated a higher prevalence of thrombocytopenia (OR 2.16, 95% CI 1.41-3.29). The DRB3-DQB2 haplotype exhibited a strong association with anti-SSB positivity (OR 4.85, 95% CI 2.57-9.5) and was inversely related to lupus nephritis (OR 0.57, 95% CI 0.34-0.95). CONCLUSIONS: This study shows how the clinical and serological complexity of SLE is associated with the genetic diversity of HLA and non-HLA regions. We thus suggest further investigation of mechanistic correlates to variations in the NCF2 gene as well as the tight association between DRB3-DQB2 haplotype and anti-SSB production.

Oct 2025Open Access

LeffersTranslational research

Autoantibody-defined subsets of patients with systemic lupus erythematosus associate with clinical manifestations, NCF2, and HLA DR3-DQ2 genotypes

INTRODUCTION: Understanding the associations between genetic markers, serological subsets and clinical manifestations in patients with Systemic lupus erythematosus (SLE) may elucidate disease mechanisms and inform personalised treatment strategies. This study aimed to classify SLE patients into distinct subsets based on autoantibody profiles and to examine associations with clinical and genetic characteristics, focusing on key risk loci. METHODS: A cohort of 846 SLE patients from the Danish SLE Gene-Environment Interaction study (SLE-GEIST) was analysed. Patients were grouped by cluster analysis of cumulative history of autoantibody positivity, and genotyped for known risk alleles, including HLA and non-HLA variants. Multinomial, multivariable logistic regression models were employed to identify associations between autoantibody subsets, clinical manifestations, and genetic markers. RESULTS: Six serological subsets with distinct characteristics were identified. The NCF2 variant was significantly associated with the subset characterised by antiphospholipid antibodies, showing an odds ratio (OR) of 2.42 (95% confidence interval [CI] 1.24-4.74) for co-positivity of anti-cardiolipin IgG and anti-beta2-glycoprotein IgG. This subset also demonstrated a higher prevalence of thrombocytopenia (OR 2.16, 95% CI 1.41-3.29). The DRB3-DQB2 haplotype exhibited a strong association with anti-SSB positivity (OR 4.85, 95% CI 2.57-9.5) and was inversely related to lupus nephritis (OR 0.57, 95% CI 0.34-0.95). CONCLUSIONS: This study shows how the clinical and serological complexity of SLE is associated with the genetic diversity of HLA and non-HLA regions. We thus suggest further investigation of mechanistic correlates to variations in the NCF2 gene as well as the tight association between DRB3-DQB2 haplotype and anti-SSB production.

Meta-Analysis

SEP 2025Kerrebijn

The genetic architecture of fibromyalgia across 2.5 million individuals

Genome-wide association study reveals 26 risk loci for fibromyalgia, suggesting neural involvement.

Sep 2025Open AccessPreprint

Preprint

Kerrebijn

The genetic architecture of fibromyalgia across 2.5 million individuals

Implication

Genome-wide association study reveals 26 risk loci for fibromyalgia, suggesting neural involvement.

Original Research

AUG 2025CarssNature

Whole-genome sequencing of 490,640 UK Biobank participants

Novel genetic insights identified in multiple ancestries within UK Biobank, suggesting advances in disease understanding.

Aug 2025Open Access

CarssNature

Whole-genome sequencing of 490,640 UK Biobank participants

Implication

Novel genetic insights identified in multiple ancestries within UK Biobank, suggesting advances in disease understanding.

Cohort Study

JUN 2025ChenLara D. Veeken

Associations of healthy lifestyle and genetic susceptibility with risks of osteoarthritis: a prospective cohort study

OBJECTIVES: To detect the associations of a healthy lifestyle and genetic susceptibility with incident OA in the UK Biobank study. METHODS: We included 314 729 participants from UK Biobank. Five modifiable lifestyle factors including weight management, diet, physical activity, sleep behaviour and sedentary behaviour were included to generate an overall lifestyle score. Genetic susceptibility was calculated by using polygenic risk score (PRS) of OA. Participants diagnosed with OA were identified by using the International Classification of Diseases (ICD)-9 and ICD-10. Covariates included age, sex, education, Townsend deprivation index, glucosamine use, analgesics use and comorbidities. Cox regression analyses were performed to examine the associations of genetic susceptibility and healthy lifestyle with incident OA. RESULTS: Adopting a more favourable lifestyle can be beneficial in significantly reducing the risk of incident total, knee and hip OA (all P < 0.01). PRS was significantly associated with greater risks of total, knee and hip OA. Compared with unfavourable lifestyle, favourable lifestyle was significantly associated with a lower risk of total OA across low [hazard ratio (HR) 0.64; 95% CI 0.58-0.70], intermediate (HR 0.59; 95% CI 0.56-0.63) and high (HR 0.58; 95% CI 0.53-0.64) genetic risk groups. Similar results were observed on knee OA and hip OA. No significant interactions were detected between lifestyle and PRS for total, knee or hip OA. CONCLUSION: These data suggest that a healthier lifestyle is consistently associated with a lower risk of OA, regardless of genetic risks. Our findings highlight the importance of adherence to an overall healthy lifestyle in attenuating the risk of OA.

Jun 2025

Level 3: Cohort Study

ChenLara D. Veeken

Associations of healthy lifestyle and genetic susceptibility with risks of osteoarthritis: a prospective cohort study

OBJECTIVES: To detect the associations of a healthy lifestyle and genetic susceptibility with incident OA in the UK Biobank study. METHODS: We included 314 729 participants from UK Biobank. Five modifiable lifestyle factors including weight management, diet, physical activity, sleep behaviour and sedentary behaviour were included to generate an overall lifestyle score. Genetic susceptibility was calculated by using polygenic risk score (PRS) of OA. Participants diagnosed with OA were identified by using the International Classification of Diseases (ICD)-9 and ICD-10. Covariates included age, sex, education, Townsend deprivation index, glucosamine use, analgesics use and comorbidities. Cox regression analyses were performed to examine the associations of genetic susceptibility and healthy lifestyle with incident OA. RESULTS: Adopting a more favourable lifestyle can be beneficial in significantly reducing the risk of incident total, knee and hip OA (all P < 0.01). PRS was significantly associated with greater risks of total, knee and hip OA. Compared with unfavourable lifestyle, favourable lifestyle was significantly associated with a lower risk of total OA across low [hazard ratio (HR) 0.64; 95% CI 0.58-0.70], intermediate (HR 0.59; 95% CI 0.56-0.63) and high (HR 0.58; 95% CI 0.53-0.64) genetic risk groups. Similar results were observed on knee OA and hip OA. No significant interactions were detected between lifestyle and PRS for total, knee or hip OA. CONCLUSION: These data suggest that a healthier lifestyle is consistently associated with a lower risk of OA, regardless of genetic risks. Our findings highlight the importance of adherence to an overall healthy lifestyle in attenuating the risk of OA.

Meta-Analysis

JUN 2025GhouseJHEP Reports

Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development

Background & Aims: The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC. Methods: We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC. Results: ) had concordant effects on HCC and biliary tract cancer. Conclusions: We identified and validated nine genetic variants associated with an increased risk of HCC development. Impact and implications: The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.

Jun 2025Open Access

Level 1: Meta-Analysis

GhouseJHEP Reports

Genome-wide meta-analysis identifies nine loci associated with higher risk of hepatocellular carcinoma development

Background & Aims: The genetic underpinnings of hepatocellular carcinoma (HCC) remain largely unknown. Thus, we aimed to identify new genetic risk loci for HCC. Methods: We performed a genome-wide association study (GWAS) meta-analysis of 11 cohorts with validation in two independent cohorts. The identified variants were tested for effects on other hepatobiliary endpoints, and on incident HCC stratified by underlying risk factors. Mendelian randomization was used to assess the causal effects of a range of traits on the risk of HCC. Results: ) had concordant effects on HCC and biliary tract cancer. Conclusions: We identified and validated nine genetic variants associated with an increased risk of HCC development. Impact and implications: The genetic underpinnings of HCC remain largely unknown. In this genome-wide association meta-analysis totaling 6,540 cases with HCC and 2.1 million controls, we identified and validated nine genetic loci to associate with the risk of HCC. A deeper insight into genetic factors that affect the risk of HCC could improve our ability to predict and ultimately prevent or treat this deadly cancer.

Original Research

MAY 2025ArnadottirNature

Sequence diversity lost in early pregnancy

Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy. Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.

May 2025Open Access

ArnadottirNature

Sequence diversity lost in early pregnancy

Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy. Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.

Original Research

MAY 2025SchwabaUniversity of Pennsylvania

Robust inference and widespread genetic correlates from a large-scale genetic association study of human personality

Personality traits describe stable differences in how individuals think, feel, and behave and how they interact with and experience their social and physical environments. We assemble data from 46 cohorts including 611K-1.14M participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), and data from 51K participants for within-family GWAS. We identify 1,257 lead genetic variants associated with personality, including 823 novel variants. Common genetic variants explain 4.8%-9.3% of the variance in each trait, and 10.5%-16.2% accounting for measurement unreliability. Genetic effects on personality are highly consistent across geography, reporter (self vs. close other), age group, and measurement instrument, and we find minimal spousal assortment for personality in recent history. In stark contrast to many other social and behavioral traits, within-family GWAS and polygenic index analyses indicate little to no shared environmental confounding in genetic associations with personality. Polygenic prediction, genetic correlation, and Mendelian randomization analyses indicate that personality genetics have widespread, potentially causal associations with a wide range of consequential behaviors and life outcomes. The genetic architecture of personality is robust and fundamental to being a human.

May 2025Open AccessPreprint

Preprint

Schwaba

Robust inference and widespread genetic correlates from a large-scale genetic association study of human personality

Personality traits describe stable differences in how individuals think, feel, and behave and how they interact with and experience their social and physical environments. We assemble data from 46 cohorts including 611K-1.14M participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), and data from 51K participants for within-family GWAS. We identify 1,257 lead genetic variants associated with personality, including 823 novel variants. Common genetic variants explain 4.8%-9.3% of the variance in each trait, and 10.5%-16.2% accounting for measurement unreliability. Genetic effects on personality are highly consistent across geography, reporter (self vs. close other), age group, and measurement instrument, and we find minimal spousal assortment for personality in recent history. In stark contrast to many other social and behavioral traits, within-family GWAS and polygenic index analyses indicate little to no shared environmental confounding in genetic associations with personality. Polygenic prediction, genetic correlation, and Mendelian randomization analyses indicate that personality genetics have widespread, potentially causal associations with a wide range of consequential behaviors and life outcomes. The genetic architecture of personality is robust and fundamental to being a human.

Meta-Analysis

MAY 2025WhiteHarvard University

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves’ disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ∼2.9 million genomes and identified 235 known and 501 novel independent variants significantly linked to thyroid diseases. We discovered genetic correlations between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases ( r 2 =0.21-0.97). Telomere maintenance genes contribute to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair, and DNA damage response genes are predominantly associated with thyroid cancer. We proposed a paradigm explaining genetic predisposition to benign and malignant thyroid nodules. We evaluated thyroid cancer polygenic risk scores (PRS) for clinical applications in thyroid cancer diagnosis. We found PRS associations with thyroid cancer risk features: multifocality, lymph node metastases, and extranodal extension.

May 2025Open AccessPreprint

Preprint

White

Global multi-ancestry genetic study elucidates genes and biological pathways associated with thyroid cancer and benign thyroid diseases

Thyroid diseases are common and highly heritable. Under the Global Biobank Meta-analysis Initiative, we performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer, benign nodular goiter, Graves’ disease, lymphocytic thyroiditis, and primary hypothyroidism. We analyzed genetic association data from ∼2.9 million genomes and identified 235 known and 501 novel independent variants significantly linked to thyroid diseases. We discovered genetic correlations between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases ( r 2 =0.21-0.97). Telomere maintenance genes contribute to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair, and DNA damage response genes are predominantly associated with thyroid cancer. We proposed a paradigm explaining genetic predisposition to benign and malignant thyroid nodules. We evaluated thyroid cancer polygenic risk scores (PRS) for clinical applications in thyroid cancer diagnosis. We found PRS associations with thyroid cancer risk features: multifocality, lymph node metastases, and extranodal extension.

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