Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Parents' experience and views on the assessment and treatment of children with OCD within the public mental health system in Iceland: a qualitative study.

PURPOSE: Obsessive-compulsive disorder (OCD) in children can lead to long-lasting symptoms and access to evidence-based evaluation and treatment is crucial for its prevention. In Iceland, the law guarantees public access to the highest quality healthcare services. To date, no study has evaluated the services available for children with OCD within the national healthcare system (NMHS). This qualitative study explored the experiences of parents navigating the Icelandic NMHS for their children with OCD. METHOD AND MATERIALS: Seven parents who had sought services within the NMHS for their children diagnosed with OCD at private clinics were interviewed using a semi-structured interview. The responses were analyzed using thematic framework analysis. RESULTS: Nineteen themes were identified, including three overarching themes and eight overarching sub-themes, and eight sub-themes within them. A prevalent theme was the giving up on the national mental healthcare system due to parents' experiences of accessing mental healthcare for their children being challenging. Other issues faced by parents included a lack of knowledge on where to seek help, inadequate evaluation of the issue, and the lack of access to psychotherapy for their children. The healthcare workers' responses and recommendations also resulted in parents seeking treatment at private clinics. CONCLUSIONS: These findings underscore the need for clearer pathways for seeking help, improved access to trained healthcare workers, and a more centralized evaluation process. These insights can potentially guide future research and policy decisions to better support families dealing with childhood OCD in Iceland.

Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index.

Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions.

The role of childhood adversity and prenatal mental health as psychosocial risk factors for adverse delivery and neonatal outcomes.

OBJECTIVE: Exposure to adverse childhood experiences (ACEs) is a significant predictor for physical and mental health problems later in life, especially during the perinatal period. Prenatal common mental disorders (PCMDs) are well-established as a risk for obstetric interventions but knowledge on combined effects of multiple psychosocial risk factors is sparse. We aim to examine a comprehensive model of ACEs and PCMDs as risk factors for poor delivery and neonatal outcomes. METHOD: With structural equation modeling, we examined direct and indirect pathways between psychosocial risk and delivery and neonatal outcomes in a prospective cohort from pregnancy to birth in Iceland. RESULTS: Exposure to ACEs increased risk of PCMDs [ß = 0.538, p < .001, CI: 0.195-1.154] and preterm delivery [ß = 0.768, p < .05, CI: 0.279-1.007)]. An indirect association was found between ACEs and increased risk of non-spontaneous delivery [ß = 0.054, p < .05, CI: 0.004-0.152], mediated by PCMDs. Identical findings were observed for ACEs subcategories. CONCLUSION: ACEs are strong predictors for mental health problems during pregnancy. Both ACEs and PCMDs diagnosis are associated with operative delivery interventions and neonatal outcomes. Findings underscore the importance of identifying high-risk women and interventions aimed at decreasing psychosocial risk during the prenatal period.

DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias.

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.

Non-Cardiac Chest Pain as a Persistent Physical Symptom: Psychological Distress and Workability.

Non-Cardiac Chest Pain (NCCP) is persistent chest pain in the absence of identifiable cardiac pathology. Some NCCP cases meet criteria for Persistent Physical Symptoms (PPS), where the symptoms are both persistent and distressing/disabling. This study aimed to identify patients that might need specialist treatment for PPS by examining cases of NCCP that meet PPS criteria. We analysed data from 285 chest pain patients that had received an NCCP diagnosis after attending an emergency cardiac department. We compared NCCP patients who did and did not meet the additional criteria for heart-related PPS and hypothesised that the groups would differ in terms of psychological variables and workability. We determined that NCCP patients who meet PPS criteria were more likely than other NCCP patients to be inactive or unable to work, reported more general anxiety and anxiety about their health, were more depressed, ruminated more, and, importantly, had a higher number of other PPS. A high proportion of NCCP patients meet PPS criteria, and they are similar to other PPS patients in terms of comorbidity and disability. This highlights the importance of focusing psychological interventions for this subgroup on the interplay between the range of physical and psychological symptoms present.

How effective psychological treatments work: mechanisms of change in cognitive behavioural therapy and beyond.

BACKGROUND: Cognitive behavioural therapy (CBT) has, in the space of 50 years, evolved into the dominant modality in psychological therapy. Mechanism/s of change remain unclear, however. AIMS: In this paper, we will describe key features of CBT that account for the pace of past and future developments, with a view to identifying candidates for mechanism of change. We also highlight the distinction between 'common elements' and 'mechanisms of change' in psychological treatment. METHOD: The history of how behaviour therapy and cognitive therapy developed are considered, culminating in the wide range of strategies which now fall under the heading of cognitive behavioural therapy (CBT). We consider how the empirical grounding of CBT has led to the massive proliferation of effective treatment strategies. We then consider the relationship between 'common factors' and 'mechanisms of change', and propose that a particular type of psychological flexibility is the mechanism of change not only in CBT but also effective psychological therapies in general. CONCLUSION: Good psychological therapies should ultimately involve supporting people experiencing psychological difficulties to understand where and how they have become 'stuck' in terms of factors involved in maintaining distress and impairment. A shared understanding is then evaluated and tested with the intention of empowering and enabling them to respond more flexibly and thereby reclaim their life.

Genetic variants associated with platelet count are predictive of human disease and physiological markers.

Platelets play an important role in hemostasis and other aspects of vascular biology. We conducted a meta-analysis of platelet count GWAS using data on 536,974 Europeans and identified 577 independent associations. To search for mechanisms through which these variants affect platelets, we applied cis-expression quantitative trait locus, DEPICT and IPA analyses and assessed genetic sharing between platelet count and various traits using polygenic risk scoring. We found genetic sharing between platelet count and counts of other blood cells (except red blood cells), in addition to several other quantitative traits, including markers of cardiovascular, liver and kidney functions, height, and weight. Platelet count polygenic risk score was predictive of myeloproliferative neoplasms, rheumatoid arthritis, ankylosing spondylitis, hypertension, and benign prostate hyperplasia. Taken together, these results advance understanding of diverse aspects of platelet biology and how they affect biological processes in health and disease.

"I'm So Tired": Fatigue as a Persistent Physical Symptom among Working People Experiencing Exhaustion Disorder.

Fatigue is widespread in the population, particularly among working people. Exhaustion disorder (ED), a clinical manifestation of burnout, is common, but, after treatment, about one-third still experience fatigue and other physical symptoms. We propose that in some instances, fatigue as a persistent physical symptom (PPS) might be a more appropriate formulation of ED patients' fatigue problems, and we suggest that ED patients who meet fatigue PPS criteria will differ from other ED patients in terms of psychological distress, non-fatigue PPSs and functional impairment. Questionnaires were sent to 10,956 members of a trade union of which 2479 (22.6%) responded. Of 1090 participants who met criteria for ED, 106 (9.7%) met criteria for fatigue as a PPS. Participants who met fatigue PPS criteria scored on average higher on measures of depression, anxiety and functional impairment and were more likely to have clinically significant scores. Moreover, they had 27 times higher odds of meeting other PPS subtypes and reported more non-fatigue PPS subtypes, suggesting a more complex health problem. Specific evidence-based interventions are available for both ED and PPSs, and therefore, it is crucial to accurately formulate the fatigue problem reported by patients to provide appropriate treatment.

Distinction between the effects of parental and fetal genomes on fetal growth.

Birth weight is a common measure of fetal growth that is associated with a range of health outcomes. It is directly affected by the fetal genome and indirectly by the maternal genome. We performed genome-wide association studies on birth weight in the genomes of the child and parents and further analyzed birth length and ponderal index, yielding a total of 243 fetal growth variants. We clustered those variants based on the effects of transmitted and nontransmitted alleles on birth weight. Out of 141 clustered variants, 22 were consistent with parent-of-origin-specific effects. We further used haplotype-specific polygenic risk scores to directly test the relationship between adult traits and birth weight. Our results indicate that the maternal genome contributes to increased birth weight through blood-glucose-raising alleles while blood-pressure-raising alleles reduce birth weight largely through the fetal genome.

Adults referred to a national ADHD clinic in Iceland: clinical characteristics and follow-up status.

OBJECTIVE: Evaluate adults referred to a national ADHD clinic, by comparing those diagnosed with those who were not, and those who screened negative and to evaluate changes among those diagnosed at follow-up. METHOD: Data obtained from 531 patients' medical records (49.7% males). One hundred thirty-six screened negative, 395 positive and 305 met diagnostic criteria for ADHD. Eighty-three of them were contacted by phone at follow-up. RESULTS: ADHD diagnosis was associated with lower educational status and more concerns expressed by parents and teachers during childhood. Participants not diagnosed with ADHD more often met diagnostic criteria for dysthymia, agoraphobia and generalized anxiety, and were more likely to be diagnosed with two or more comorbid disorders. At follow-up, all reported a significant reduction of ADHD symptoms, irrespective of medication, but the medicated participants reported fewer symptoms of inattention and better functioning in daily life. CONCLUSION: Adults referred to ADHD clinics may have multiple mental health problems, regardless of whether they receive ADHD diagnosis or not. This could have implications for differential diagnoses of ADHD in adults and emphasises the need to have appropriate treatment available for both groups. Psychoeducation about ADHD may be very helpful in decreasing anxiety and ADHD symptoms.

Cognitive analysis of specific threat beliefs and safety-seeking behaviours in generalised anxiety disorder: revisiting the cognitive theory of anxiety disorders.

BACKGROUND: Generalised anxiety disorder (GAD) has been an uneasy member of the anxiety disorders group since its inclusion in the third edition of the DSM. Multiple theories and treatment protocols for GAD and its defining symptom, excessive worry, have comparable efficacy in treating GAD symptoms. Crucially, these theories of GAD and excessive worry fail to explain when and why worry is excessive and when it is adaptive. AIMS: In this paper we propose a cognitive behavioural account of the difference between excessive and adaptive states of worry and explore the theme of threat and the function of safety-seeking behaviours as seen in GAD. Specifically, we incorporate the concept of inflated responsibility in a cognitive behavioural analysis of threat appraisal and safety-seeking behaviours in excessive worry and GAD. CONCLUSION: It is proposed that when worry is used as a strategy intended to increase safety from perceived social or physical threat then it should be conceptualised as a safety-seeking behaviour. However, when worry is used as a strategy to solve a problem which the person realistically can resolve or to deal explicitly with the feeling of anxiety then it functions as an adaptive coping behaviour. We also propose that the theme of threat in GAD centres on an inflated sense of responsibility for external everyday situations, and the function of safety-seeking behaviours is to attain certainty that responsibility has been fulfilled. The clinical implications of this cognitive behavioural analysis of excessive worry are discussed, as well as future research directions.

Genetic insight into sick sinus syndrome.

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

[Prevalence of persistent physical symptoms and association with depression, anxiety and health anxiety in Iceland].

INTRODUCTION: Persistent physical symptoms that are medically unexplained can result in significant functional impairment. The aim of this study was to estimate the prevalence of persistent physical symptoms among people seeking primary healthcare in Reykjavík, Iceland, how they relate to functional impairment, symptoms of depression, general anxiety and health anxiety, and estimate the proportion of people with such symptoms who would likely benefit from psychological treatment. MATERIALS AND METHODS: Questionnaires measuring persistent physical symptoms, functional impairment, and symptoms of depression, general anxiety and health anxiety were administered to 106 patients attending two primary healthcare clinics. RESULTS: The prevalence of persistent physical symptoms was 27.4% among the primary care patients and they had a strong relationship to symptoms of mental disorders. Participants with persistent physical symptoms were 8 times more likely to have clinical levels of depression and general anxiety than participants without such symptoms, 4 times more likely to have clinical levels of health anxiety and 13 times more likely to have clinical levels of functional impairment. At least two-thirds of participants with persistent physical symptoms would likely benefit from psychological treatment. CONCLUSION: The prevalence of persistent physical symptoms among health care patients in the capital area of Iceland is in line with previous studies. Similarly, the strong relationship between persistent physical symptoms and symptoms of depression and anxiety corresponds to previous studies. It is likely that at least two out of three patients with persistent physical symptoms would benefit from psychological treatment. Transdiagnostic cognitive behavioural therapy for persistent physical symptoms might be particularly useful as is focuses on the interplay between physical and mental symptoms.

Evaluation of mechanism of change in transdiagnostic cognitive behaviour therapy using single case experimental design.

BACKGROUND AND OBJECTIVES: Transdiagnostic mechanisms of change (txMOC) specific to cognitive behaviour therapy are poorly understood. Salkovskis (1996) proposed one such mechanism in terms of the shift towards an alternative, less negative view of their problems or cognitive flexibility. This hypothesis has been described as involving a shift in beliefs, from "theory A″ to "theory B". The objective of this research was to evaluate this hypothesis. METHODS: Effectiveness of a novel txCBT and temporal changes in process and symptom measures were evaluated using a non-concurrent multiple baseline design and Tau-U calculations with thirteen participants (five with obsessive-compulsive disorder, two with panic disorder with agoraphobia and six with major depressive disorder). As a secondary analysis authors calculated Kendall's - Tau correlation between process and symptom measures, performed the Wilcoxon signed-rank test to assess treatment modules effect on negative thought and calculated Reliable change index (RCI). RESULTS: The txCBT was clearly effective for eight participants. The results varied dependent on the stimuli evaluated as negative or threatening. Level and trend of the ratings of belief in theory A followed the level and trend of symptom measures to a greater extent than the (inverse) level and trend of belief in theory B. LIMITATIONS: Only thirteen participants were recruited and evaluated. CONCLUSIONS: The results are consistent with the view that effective treatment may involve a txMOC characterized by the ability to shift from a relatively fixed negative view of their experience to a less negative psychologically focused alternative.

Genetic insight into sick sinus syndrome.

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.