A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Sex differences in clinical characteristics of migraine and its burden: a population-based study.

BACKGROUND AND PURPOSE: Understanding migraine in a sex-specific manner is crucial for improving clinical care, diagnosis and therapy for both females and males. Here, data on sex differences are provided in the presentation of migraine in a large European-based population cohort, which is representative of the general population. METHODS: A population-based study of 62,672 Danish blood donors (both present and previous donors), of whom 12,658 had migraine, was performed. All participants completed a 105-item diagnostic migraine questionnaire sent via an electronic mailing system (e-Boks) between May 2020 and August 2020. The questionnaire allowed for correct diagnosis of migraine according to the International Classification of Headache Disorders, third edition. RESULTS: The migraine questionnaire was in-cohort validated and had a positive predictive value of 97% for any migraine, a specificity of 93% and a sensitivity of 93%. There were 9184 females (mean age 45.1 years) and 3434 males (mean age 48.0 years). The 3-month prevalence of migraine without aura was 11% in females and 3.59% in males. The 3-month prevalence of migraine with aura was 1.72% in females and 1.58% in males. In females, the age-related 3-month prevalence of migraine without aura increased markedly during childbearing age. In males, migraine both with and without aura showed less age variation. Females had a higher frequency of migraine attacks (odds ratio [OR] 1.22) but a lower frequency of non-migraine headaches (OR = 0.35). Females also had a greater intensity of pain, more unilateral and pulsatile pain, and exacerbation by physical activity (OR = 1.40-1.49) as well as more associated symptoms (OR = 1.26-1.98). Females carried 79% of the total migraine disease burden, which was almost exclusively driven by migraine without aura (77%), whilst there was no sex difference in the disease burden of migraine with aura. CONCLUSION: Females have more severe disease, resulting in a much higher migraine disease burden than indicated by prevalence alone.

The Social and Psychological Impact of Acne Treatment: A Cross-Sectional Study of Blood Donors.

BACKGROUND: Acne in adolescence and adulthood is believed to have a long-term impact on socioeconomic status (SES) and health-related quality-of-life (HRQoL) in adults. OBJECTIVE: To estimate the cross-sectional prevalence of medically treated (MedTreAc) and untreated acne (UnTreAc) and to characterize its long-term impact in adults. METHODS: A nationwide cross-sectional study on 17 428 blood donors aged 18-35 was performed. Associations among acne and HRQoL, depressive symptoms, total income, and SES were investigated via linear/logistic/multinomial logistic regression analyses adjusted for relevant covariables. HRQoL was measured by the Short Form-12, and depressive symptoms by the Major Depression Inventory. The data were self-reported. RESULTS: Of the participants, 3591 (20.6%) and 1354 (7.8%) identified as the MedTreAc and UnTreAc phenotype, respectively. Neither phenotype was associated with a long-term impact on total income, but the MedTreAc group was associated with being an apprentice/student (OR = 1.26; 95% CI: 1.12, 1.42; P = 1.3×10-4) or high skill-level employee (OR = 1.22, 95% CI: 1.07; 1.39, P = .0023), while self-employment was more common for those with UnTreAc (OR = 1.53; 95% CI: 1.12, 2.06, P = .0061). Additionally, the UnTreAc group was associated with a lower mental HRQoL (SF-12 mental component summary score -1.05, 95% CI: -1.56, -0.54; P = 1.4×10-9) and increased odds ratio of depressive symptoms (OR = 1.44; 95% CI: 1.00, 2.02, P = .046). CONCLUSION: In this population of blood donors, the cumulative prevalence of MedTreAc and UnTreAc were 20.6% and 7.8%, respectively. Untreated acne had a long-term impact on psychosocial well-being in adulthood. It was associated with lower mental HRQoL and higher occurrence of depressive symptoms. Acne was not associated with a lower salary or SES.

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.

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.

Compartmental immunophenotyping in COVID-19 ARDS: A case series.

BACKGROUND: Severe immunopathology may drive the deleterious manifestations that are observed in the advanced stages of coronavirus disease 2019 (COVID-19) but are poorly understood. OBJECTIVE: Our aim was to phenotype leukocyte subpopulations and the cytokine milieu in the lungs and blood of critically ill patients with COVID-19 acute respiratory distress syndrome (ARDS). METHODS: We consecutively included patients less than 72 hours after intubation following informed consent from their next of kin. Bronchoalveolar lavage fluid was evaluated by microscopy; bronchoalveolar lavage fluid and blood were assessed by 10-color flow cytometry and a multiplex cytokine panel. RESULTS: Four mechanically ventilated patients (aged 40-75 years) with moderate-to-severe COVID-19 ARDS were included. Immature neutrophils dominated in both blood and lungs, whereas CD4 and CD8 T-cell lymphopenia was observed in the 2 compartments. However, regulatory T cells and TH17 cells were found in higher fractions in the lung. Lung CD4 and CD8 T cells and macrophages expressed an even higher upregulation of activation markers than in blood. A wide range of cytokines were expressed at high levels both in the blood and in the lungs, most notably, IL-1RA, IL-6, IL-8, IP-10, and monocyte chemoattactant protein-1, consistent with hyperinflammation. CONCLUSION: COVID-19 ARDS exhibits a distinct immunologic profile in the lungs, with a depleted and exhausted CD4 and CD8 T-cell population that resides within a heavily hyperinflammatory milieu.

The impact of health-related quality of life and depressive symptoms on blood donor career-Results from the Danish blood donor study.

BACKGROUND: Blood donors report better health-related quality of life (HRQL) than non-donors. Likewise, donors reporting good health are less likely to stop donating and have a higher donation frequency. This is evidence of the healthy donor effect (HDE). This study is the first to investigate the impact of HRQL and depressive symptoms on subsequent donor career. STUDY DESIGN AND METHODS: Prospective cohort study includes 102,065 participants from the Danish Blood Donor Study applying the 12-item short-form health survey (SF-12) measuring a mental (MCS) and a physical component score (PCS) and the Major Depression Inventory (MDI). Poisson and Cox regression models were used to assess the effect of SF-12 and MDI scores on donation frequency and donor cessation. Higher MCS/PCS scores indicate good HRQL, while higher MDI score indicates higher experience of depressive symptoms. RESULTS: For both sexes, MCS was positively correlated with donation frequency for up to 5 years, and similarly for PCS among women. A negative correlation between MDI score and donation frequency in the year following assessment was observed only among men. No correlation was observed among women. An increase in both MCS and PCS was associated with a lower risk of donation cessation in both sexes, while an increase in MDI score was only associated with an increased risk of donation cessation in men. CONCLUSION: MCS, PCS, and MDI score affect donor career. Thus, adjusting for donation frequency may reduce HDE-bias in donor health research. However, because of the small effect sizes, other ways of quantifying HDE may be beneficial.

Risk of Hidradenitis Suppurativa Comorbidities Over Time: A Prospective Cohort Study of Danish Blood Donors.

Hidradenitis suppurativa is a common recurrent inflammatory skin disease. It is associated with multiple comorbidities whose temporal relationships are unknown due to long diagnostic delays. This study of otherwise healthy blood donors with self-reported symptoms of hidradenitis suppurativa investigated the temporal relationships of comorbidities. A prospective survival analysis on a nationwide cohort of blood donors, using registry data on drug prescription, was used to calculate the hazard ratio of time until first prescription of medical treatment for the following hidradenitis suppurativa-related comorbidities: heart disease, diabetes, depression, thyroid disease and pain. Hidradenitis suppurativa status was determined by a validated questionnaire, and the survival analysis was adjusted for age, sex, body mass index, smoking status and having an International Classification of Diseases Version 10 (ICD-10) diagnosis of hidradenitis suppurativa. Of the participants, 1,012 reported hidradenitis suppurativa symptoms, and these symptoms increased the hazard ratio of antidepressants (1.73, 95% confidence interval 1.17-2.56, p ≈ 0.006) and analgesics (hazard ratio 1.24, 95% confidence interval 1.11-1.39, p < 0.001). Pain and depression are the first comorbidities to present in hidradenitis suppurativa pathogenesis.

Epidemiology of Hyperhidrosis in Danish Blood Donors.

The risk factors and disease implications of hyper-hidrosis are unknown. The objectives of this retrospective cohort study were to estimate the prevalence of hyperhidrosis and to compare demographic, life-style, and socioeconomic parameters in blood donors with and without self-reported or hospital-diagnosed hyperhidrosis. The study included blood donors from the Danish Blood Donor Study for the period 2010-2019. Registry data were collected from Statistics Denmark. Overall, 2,794 of 30,808 blood donors (9.07%; 95% confidence interval (95% CI) 8.75-9.40) had self- reported hyperhidrosis and 284 of 122,225 (0.23%; 95% CI 0.21-0.26) had hospital-diagnosed hyperhidrosis. Self-reported hyperhidrosis was associated with smoking (odds ratio (OR) 1.17; 95% CI 1.05-1.31), overweight (OR 1.72; 95% CI 1.58-1.87), "unemployed" (OR 1.60; 95% CI 1.24-2.08), "short education" (OR 0.76; 95% CI 0.64-0.90), and lower income (beta-coefficient -26,121; 95% CI -37,931, -14,311). Hospital-diagnosed hyperhidrosis did not differ from controls. Thus, self-reported hyperhidrosis was associated with potential hyperhidrosis risk factors (smoking, overweight) and disease implications (unemployment, low education level and income).

Cytokine Autoantibodies Are Associated with Infection Risk and Self-Perceived Health: Results from the Danish Blood Donor Study.

The presence of naturally occurring cytokine-specific autoantibodies (c-aAb) in humans is well established, as well as associations to selected pathologies. However, the overall influence of c-aAb on immunocompetence remains largely unknown. In this paper, we performed a large-scale investigation of c-aAb association with infection risk. A cohort of healthy Danish blood donors was screened for c-aAb against IL-1α, IL-6, IL-10, IFNα, and GM-CSF using a Luminex-based multiplex assay, and results were linked to data from the Danish National Prescription Registry. The filing of an antimicrobial prescription following c-aAb measurement was used as a proxy for impaired immunocompetence. We found that c-aAb against pro-inflammatory cytokines IFNα and GM-CSF tended to associate with increased risk of prescription filings in women, whereas antibodies against anti-inflammatory IL-10 were associated with a lower predicted risk of antimicrobial prescriptions, as well as higher self-perceived health scores. We also observed an association of cumulative c-aAb presence with prescription risk. Our data show that cytokine autoantibodies in healthy individuals associate with various proxies for immunomodulation, with the exact association dependent on the pattern of pro- or anti-inflammatory cytokines targeted. This suggests that c-aAb may express cytokine-modulatory properties in healthy individuals and may be critical to further investigate as biomarkers of immunodeficiency.

The donors perceived positive and negative effects of blood donation.

BACKGROUND: Occasionally blood donation has a negative influence on some donors, while others express feelings of increased energy or wellbeing after donation. Some donors even report symptoms such as headache or feelings of unease indicating "it is time to donate blood again." This study aims to determine symptoms and frequencies of blood donors experiencing positive and negative effects of blood donation, and study possible associations with sex, age, body mass index, smoking status, and hemoglobin level. STUDY DESIGN AND METHODS: We developed and validated a questionnaire with eight predefined physical and psychological symptoms related to blood donation using a 5-point Likert Scale. Participants in The Danish Blood Donor Study were asked to indicate if they experienced the present symptom prior to and/or after the donation. RESULTS: A total of 6,073 donors were included. Of the donors, 61% experienced one or more effects of blood donation. Positive effects were experienced by 18% of the donors, 29% experienced negative effects, and 14% experienced both. Most notable positive effects were alleviated headache (14%), feeling lighter (14%), and less tiredness (7%). Most notable negative effects were less energy (25%), more dizziness (22%), and more tiredness (21%). Logistic regression analysis revealed that positive effects were more likely among donors with higher BMI, older donors, and smokers. Negative effects were more likely among younger donors, donors with lower BMI, and among female donors. CONCLUSION: Analyses indicate that susceptibility to blood donation effects varies by BMI, sex, smoking status, and age, and therefore should be taken into consideration when informing donors about potential effects of blood donation.

Prevalence and socio-demographic characteristics of persons who have never had a headache among healthy voluntary blood donors - a population-based study.

INTRODUCTION: Headache is an extremely prevalent disorder with a lifetime prevalence of 90-99%. However, a small fraction of people never experiences a headache. Research on people without headache could uncover protective factors in headache, but to our knowledge no study on headache-free individuals has been published. We aim to estimate the prevalence of headache-free individuals among Danish blood donors, and to describe the socio-demographics and health factors of headache-free participants. MATERIALS AND METHODS: In all, 38,557 healthy volunteers were recruited as part of the Danish Blood Donor Study. Headache-free participants were identified based on the question "Have you ever experienced a headache of any kind?". Utilising the Danish registries and self-reported questionnaires, we analysed socio-demographic and lifestyle factors using logistic regression adjusted for age and sex. RESULTS: The prevalence of headache-free individuals was 4.1% (n = 1362) with a female-male ratio of 1:2.2. To be headache free was significantly associated with an employment status as a student, a low level of income and a regular alcohol consumption. DISCUSSION: The prevalence of headache-free individuals was comparable to population-wide studies of headache. To be headache free was not associated with a high socio-economic status. Further studies on people without headache will hopefully reveal protective factors in headache, and this novel approach might be useful in other very prevalent disorders.

Attitudes of stakeholders in psychiatry towards the inclusion of children in genomic research.

BACKGROUND: Genomic sequencing of children in research raises complex ethical issues. This study aims to gain more knowledge on the attitudes towards the inclusion of children as research subjects in genomic research and towards the disclosure of pertinent and incidental findings to the parents and the child. METHODS: Qualitative data were collected from interviews with a wide range of informants: experts engaged in genomic research, clinical geneticists, persons with mental disorders, relatives, and blood donors. Quantitative data were collected from a cross-sectional web-based survey among 1227 parents and 1406 non-parents who were potential stakeholders in psychiatric genomic research. RESULTS: Participants generally expressed positive views on children's participation in genomic research. The informants in the qualitative interviews highlighted the age of the child as a critical aspect when disclosing genetic information. Other important aspects were the child's right to an autonomous choice, the emotional burden of knowing imposed on both the child and the parents, and the possibility of receiving beneficial clinical information regarding the future health of the child. Nevertheless, there was no consensus whether the parent or the child should receive the findings. A majority of survey stakeholders agreed that children should be able to participate in genomic research. The majority agreed that both pertinent and incidental findings should be returned to the parents and to the child when of legal age. Having children does not affect the stakeholder's attitudes towards the inclusion of children as research subjects in genomic research. CONCLUSION: Our findings illustrate that both the child's right to autonomy and the parents' interest to be informed are important factors that are found valuable by the participants. In future guidelines governing children as subjects in genomic research, it would thus be essential to incorporate the child's right to an open future, including the right to receive information on adult-onset genetic disorders.

Large-scale study of Toxoplasma and Cytomegalovirus shows an association between infection and serious psychiatric disorders.

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

Genetic factors influencing hemoglobin levels in 15,567 blood donors: results from the Danish Blood Donor Study.

BACKGROUND: Blood donors have an increased risk of low hemoglobin (Hb) levels due to iron deficiency. Therefore, knowledge of genetic variants associated with low Hb could facilitate individualized donation intervals. We have previously reported three specific single-nucleotide polymorphisms that were associated with ferritin levels in blood donors. In this study, we investigated the effect of these single-nucleotide polymorphisms on Hb levels in 15,567 Danish blood donors. STUDY DESIGN AND METHODS: We studied 15,567 participants in the Danish Blood Donor Study. The examined genes and single-nucleotide polymorphisms were 1) TMPRSS6, involved in regulation of hepcidin: rs855791; 2) HFE, associated with hemochromatosis: rs1800562 and rs1799945; 3) BTBD9, associated with restless leg syndrome: rs9357271; and 4) TF, encoding transferrin: rs2280673 and rs1830084. Associations with Hb levels and risk of Hb deferral were assessed in multivariable linear and logistic regression models. RESULTS: The HFE,rs1800562 G-allele and the HFE rs1799945 C-allele were associated with lower Hb levels in men and women, and with an increased risk of Hb below 7.8 mmol/L (12.5 g/dL) in women. Only the rs1799945 C-allele increased the risk of Hb below 8.4 mmol/L (13.5 g/dL) in men. In TMPRSS6, the rs855791 T-allele was associated with lower Hb levels in both men and women, and with an increased risk of low Hb among women. CONCLUSION: With this study we demonstrate that HFE and TMPRSS6 are associated with Hb levels and risk of Hb below the limit of deferral. Thus, genetic testing may be useful in a future assay for personalized donation intervals.

Richness of human gut microbiome correlates with metabolic markers.

We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities.

Comorbidity of migraine with ADHD in adults.

BACKGROUND: Migraine and Attention Deficit and Hyperactivity Disorder (ADHD) have been found to be associated in child and adolescent cohorts; however, the association has not been assessed in adults or otherwise healthy population. Assessing the comorbidity between ADHD and migraine may clarify the etiopathology of both diseases. Thus, the objective is to assess whether migraine (with and without visual disturbances) and ADHD are comorbid disorders. METHODS: Participants from the Danish Blood Donor Study (N = 26,456, age 18-65, 46% female) were assessed for migraine and ADHD using the ASRS ver 1.1 clinically validated questionnaire and self-reported migraine in a cross-sectional study. Logistic regression was used to examine the comorbidity between migraine and ADHD, and their associated endophenotypes. RESULTS: Migraine was strongly associated with ADHD (OR = 1.8, 95% CI = 1.5-2.1), (238/6152 vs 690/19,376). There was a significant interaction between age and gender, with comorbidity increasing with age and female sex. Post-hoc analysis showed that migraine with visual disturbance was generally associated with a marginally higher risk of ADHD and this was independent of ADHD endophenotypes. CONCLUSION: Migraine and ADHD were demonstrated to be comorbid disorders; the association with ADHD was most prominent for participants with migraine with visual disturbances. Future studies will elucidate which genetic and environmental factors contribute to migraine-ADHD comorbidity.

Stakeholders in psychiatry and their attitudes toward receiving pertinent and incident findings in genomic research.

Increasingly more psychiatric research studies use whole genome sequencing or whole exome sequencing. Consequently, researchers face difficult questions, such as which genomic findings to return to research participants and how. This study aims to gain more knowledge on the attitudes among potential research participants and health professionals toward receiving pertinent and incidental findings. A cross-sectional online survey was developed to investigate the attitudes among research participants toward receiving genomic findings. A total of 2,637 stakeholders responded: 241 persons with mental disorders, 671 relatives, 1,623 blood donors, 74 psychiatrists, and 28 clinical geneticists. Stakeholders wanted both pertinent findings (95%) and incidental findings (91%) to be made available for research participants. The majority (77%) stated that researchers should not actively search for incidental findings. Persons with mental disorders and relatives were generally more positive about receiving any kind of findings than clinical geneticists and psychiatrists. Compared with blood donors, persons with mental disorders reported to be more positive about receiving raw genomic data and information that is not of serious health importance. Psychiatrists and clinical geneticists were less positive about receiving genomic findings compared with blood donors. The attitudes toward receiving findings were very positive. Stakeholders were willing to refrain from receiving incidental information if it could compromise the research. Our results suggest that research participants consider themselves as altruistic participants. This study offers valuable insight, which may inform future programs aiming to develop new strategies to target issues relating to the return of findings in genomic research.

Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study.

BACKGROUND: Many biologic functions depend on sufficient iron levels, and iron deficiency is especially common among blood donors. Genetic variants associated with iron levels have been identified, but the impact of genetic variation on iron levels among blood donors remains unclear. STUDY DESIGN AND METHODS: The effect of six single-nucleotide polymorphisms (SNPs) on ferritin levels in 14,126 blood donors were investigated in four genes: in Human Hemochromatosis Protein gene (HFE; rs1800562 and rs179945); in Transmembrane Protease gene, Serine 6 (TMPRSS6-regulating hepcidin; rs855791); in BTB domain containing protein gene (BTBD9-associated with restless legs syndrome; rs9357271); and in the Transferrin gene (TF; rs2280673 and rs1830084). Multiple linear and logistic regression analyses were used to evaluate the effect of each SNP on ferritin levels and the risk of iron deficiency (ferritin < 15 ng/mL). RESULTS: In HFE, the G-allele of rs1800562 was associated with lower iron stores in both sexes. This was also true for the C-allele of rs179945, but in men only. Also, the T-allele of TMPRSS6 rs855791 was negatively associated with iron stores in men. Homozygocity for C in rs1799945 was associated with iron deficiency in women. Results for all other genetic variants were insignificant. CONCLUSION: Genetic variants associated with hemochromatosis may protect donors against depleted iron stores. In addition, we showed that presence of the T-allele at rs855791 in TMPRSS6 was associated with lower iron stores in men.

A human gut microbial gene catalogue established by metagenomic sequencing.

To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.