A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways.

Background: The contributions of genetic and environmental risk factors to hidradenitis suppurativa (HS) are both poorly understood.

Objective: To identify sequence variants that associate with HS and determine the contribution of environmental risk factors and inflammatory diseases to HS pathogenesis.

Methods: A genome-wide association meta-analysis of 4814 HS cases (Denmark: 1977; Iceland: 1266; Finland: 800; UK: 569; and US: 202) and 1.

Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease.

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.

Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination.

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.

Variants at the Interleukin 1 Gene Locus and Pericarditis.

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.

Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis.

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.

Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, , , and / at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR).

Sequence variant affects GCSAML splicing, mast cell specific proteins, and risk of urticaria.

Urticaria is a skin disorder characterized by outbreaks of raised pruritic wheals. In order to identify sequence variants associated with urticaria, we performed a meta-analysis of genome-wide association studies for urticaria with a total of 40,694 cases and 1,230,001 controls from Iceland, the UK, Finland, and Japan. We also performed transcriptome- and proteome-wide analyses in Iceland and the UK.

Sequence variants affecting voice pitch in humans.

The genetic basis of the human vocal system is largely unknown, as are the sequence variants that give rise to individual differences in voice and speech. Here, we couple data on diversity in the sequence of the genome with voice and vowel acoustics in speech recordings from 12,901 Icelanders. We show how voice pitch and vowel acoustics vary across the life span and correlate with anthropometric, physiological, and cognitive traits.

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

Objectives: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis.

Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis.

Background And Aims: The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration.

Method And Results: We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression.

Genetic architecture of band neutrophil fraction in Iceland.

The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders.

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset.

Objectives: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets.

Methods: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen).