Publications by authors named "Hilma Holm"

Article Synopsis
  • Dilated cardiomyopathy (DCM) is a major cause of heart failure, and this study analyzes genetic factors by examining 14,256 DCM cases and 36,203 participants from the UK Biobank for related traits.
  • Researchers discovered 80 genomic risk loci and pinpointed 62 potential effector genes tied to DCM, including some linked to rare variants.
  • The study uses advanced transcriptomics to explore how cellular functions contribute to DCM, showing that polygenic scores can help predict the disease in the general population and emphasize the importance of genetic testing and development of precise treatments.
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Mendelian Randomization studies indicate that BMI contributes to various diseases, but it's unclear if this is entirely mediated by BMI itself. This study examines whether disease risk from BMI-associated sequence variants is mediated through BMI or other mechanisms, using data from Iceland and the UK Biobank. The associations of BMI genetic risk score with diseases like fatty liver disease, knee replacement, and glucose intolerance were fully attenuated when conditioned on BMI, and largely for type 2 diabetes, heart failure, myocardial infarction, atrial fibrillation, and hip replacement.

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  • Researchers analyzed genetic data from nearly 130,000 cancer patients and over 730,000 healthy controls to identify variants linked to cancer risk across 22 cancer types.
  • Four high-risk genes were found: BIK (prostate cancer), ATG12 (colorectal cancer), TG (thyroid cancer), and CMTR2 (lung cancer and melanoma).
  • Additionally, two genes, AURKB (general cancer risk) and PPP1R15A (breast cancer), were associated with decreased cancer risk, indicating potential pathways for cancer prevention strategies.
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Background: Signal transducer and activator of transcription 6 (STAT6) is central to type 2 (T2) inflammation, and common noncoding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment.

Objective: We sought to test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture.

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Background: The essential hypertension phenotype results from an interplay between genetic and environmental factors. The influence of lifestyle exposures such as excess adiposity, alcohol consumption, tobacco use, diet, and activity patterns on blood pressure (BP) is well established. Additionally, polygenic risk scores for BP traits are associated with clinically significant phenotypic variation.

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  • Immunoglobulin G (IgG) is the primary type of antibody in human blood and exists in four subclasses (IgG1 to IgG4), which are influenced by specific genes.
  • A genome-wide association study involving 4,334 adults and 4,571 children identified ten new variants and confirmed four known variants linked to IgG subclass levels, affecting conditions like asthma and autoimmune diseases.
  • Significant links were found between certain genetic allotypes and specific IgG subclasses, with notable findings showing that lower IgG4 levels can both protect against childhood asthma and increase the risk of inflammatory bowel disease.
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  • The study aims to investigate the genetic factors associated with accessory atrioventricular pathways (APs) and related heart rhythm disorders using a genome-wide association study (GWAS).
  • It involved analyzing genetic data from over 1,200,000 control individuals and 2,310 individuals with APs from multiple countries and various health databases.
  • Key findings revealed three significant genetic variants linked to APs, particularly in specific genes (CCDC141 and SCN10A), with implications for understanding conditions like paroxysmal supraventricular tachycardia (PSVT).
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Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM.

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  • - Parkinson's disease (PD) is a serious neurodegenerative disorder, and rising cases emphasize the need to identify factors that can be changed to reduce risk.
  • - A study involving 8,647 PD patients and 777,693 controls identified a new link between rare ITSN1 gene variants and PD, supported by other research databases.
  • - The research suggests that issues with Rho GTPases and synaptic vesicle transport might play a role in PD development, indicating potential new treatment strategies.
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Gene promoter and enhancer sequences are bound by transcription factors and are depleted of methylated CpG sites (cytosines preceding guanines in DNA). The absence of methylated CpGs in these sequences typically correlates with increased gene expression, indicating a regulatory role for methylation. We used nanopore sequencing to determine haplotype-specific methylation rates of 15.

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encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of in mice results in sinus pauses and bradycardia and morpholino knockdown of zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy.

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Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported.

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We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism.

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  • Genome-wide association studies (GWASs) analyzed data from over 41,000 infertility cases and 687,000 controls, identifying 21 genetic risk loci for infertility, with 12 previously unreported.
  • The study found significant genetic correlations between female infertility and conditions like endometriosis and polycystic ovary syndrome, suggesting interactions between genetic risk factors.
  • Exome sequencing revealed that women with rare testosterone-lowering variants are at higher risk for infertility, yet no general correlation between reproductive hormones and infertility was found, highlighting a complex genetic landscape.
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Background: The presence of coronary plaques with high-risk characteristics is strongly associated with adverse cardiac events beyond the identification of coronary stenosis. Testing by coronary computed tomography angiography (CCTA) enables the identification of high-risk plaques (HRP). Referral for CCTA is presently based on pre-test probability estimates including clinical risk factors (CRFs); however, proteomics and/or genetic information could potentially improve patient selection for CCTA and, hence, identification of HRP.

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Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits.

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X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1.

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Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood.

Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis.

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Article Synopsis
  • - The study aimed to assess whether certain genetic variations in the GIP receptor might increase fracture risk or lower bone mineral density (BMD) in people managing obesity through weight loss.
  • - Researchers analyzed three specific gene variants and a group of predicted loss-of-function variants across a large population of up to 1.2 million participants, examining their correlation to different types of fractures and BMD measurements.
  • - The findings indicated that none of the examined gene variants were linked to a higher risk of fractures or lower BMD, suggesting that these genetic factors do not adversely affect bone health in the context of obesity treatment.
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Aims: Hypertension is a major modifiable cause of morbidity and mortality that affects over 1 billion people worldwide. Blood pressure (BP) traits have a strong genetic component that can be quantified with polygenic risk scores (PRSs). To date, the performance of BP PRSs has mainly been assessed in adults, and less is known about polygenic hypertension risk in childhood.

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Background: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking.

Methods: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.

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Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants.

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  • Migraine is a complicated neurovascular condition with varying symptoms, traditionally studied as a single type in genome-wide association studies (GWAS), but this research focuses on two main subtypes: migraine with aura (MA) and migraine without aura (MO).
  • The study analyzed large datasets from six European populations, identifying four new gene variants associated with MA and classifying 13 variants for MO, highlighting a significant frameshift variant in PRRT2 linked to MA and epilepsy.
  • Additionally, testing on rare variants showed that loss-of-function mutations in SCN11A provide strong protection against migraine, while another variant affecting KCNK5 offers large protection against both migraine and brain aneurysms, suggesting new avenues for treatment.
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