Evidence of gene-gene interaction in hidradenitis suppurativa: a nationwide registry study of Danish twins.

BACKGROUND: Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease that, apart from rare causative loss-of-function mutations, has a widely unknown genetic aetiology. OBJECTIVES: To estimate the relative importance of genetic and environmental factors underlying susceptibility to HS. METHODS: Via the Danish Twin Registry and the Danish National Patient Registry we pulled together information on zygosity with that of HS status. Cases of HS were identified by the International Classification of Diseases (ICD)-8 (705·91) and ICD-10 (L73·2). Heritability was assessed by the classic biometric model and the possibility of gene-gene interaction via the multilocus modelling approach. RESULTS: Among 100 044 registered twins, we found 170 twins (from 163 pairs) diagnosed with HS. The seven concordant pairs were all monozygotic. Monozygotic twins had a case-wise concordance rate of 28% [95% confidence interval (CI) 7-49], corresponding to a familial risk of 73 (95% CI 13-133) times that of the background population. The biometrical modelling suggested a heritability of 0·80 (95% CI 0·67-0·93), and the multilocus index estimate was 230 (95% CI 60-400). This is highly indicative of gene-gene interactions, with the possibility of up to six interacting loci. CONCLUSIONS: This twin study was substantially larger and employed a more valid phenotype than previous studies. Genetics account for the majority of HS susceptibility, and HS is most likely caused by gene-gene interactions rather than monogenetic mutations or solely additive genetic factors. New approaches aimed at assessing potential interactions at a single-nucleotide polymorphism (SNP)-SNP level should be implemented in future HS genome-wide association studies.

Impaired fecundity as a marker of health and survival: a Danish twin cohort study.

STUDY QUESTION: Is fecundity, measured as self-reported time to first pregnancy (TTP), a marker for subsequent health and survival? SUMMARY ANSWER: Long TTP was a marker for increased mortality among women and higher hospitalization rates for both women and men. WHAT IS KNOWN ALREADY: Poor semen quality has been linked to increased mortality and morbidity from a wide range of diseases. Associations among fecundity, health and survival among women are still uncertain and studies on actual measures of fecundity and health outcomes are rare. STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study of 7825 women and 6279 men, aged 18 and above with measures on first TTP, who participated in one of the Danish nation-wide twin surveys in 1994 (twins born 1953-1976) and 1998 (twins born 1931-1952). They were followed-up for mortality and hospital admissions from the interview until 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twins were identified in the Danish Twin Registry and linked to Danish registers. TTP was restricted to the first pregnancy as a categorical outcome with cut-off points at 2, 10 and 18 months. We analysed the association between TTP and survival using a Cox proportional hazards model estimating hazards ratios (HRs) with 95% confidence intervals (CIs). Fine-Gray survival models were used to estimate sub-hazard ratios for specific causes of death allowing for competing risks. Using negative binomial regression, we estimated incidence rate ratios (IRRs) with 95% CIs for all-cause and cause-specific hospitalizations. All analyses were stratified by sex and adjusted for age at interview, birth cohorts, age at first attempt to become pregnant, smoking, years in school and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: In the total study population, 49.9% of women and 52.7% of men reported a TTP of less than 2 months, 30.8% of women and 29.6% of men reported a TTP of 2-9 months, 6.6% of women and 5.7% of men reported a TTP of 10-17 months, and 13.3% of women and 12.0% of men reported a TTP of 18 months or more. Among 1305 deaths, we found a higher mortality for women (HR = 1.46; 95% CI 1.15, 1.87) with a TTP of ≥18 months relative to those with a TTP of <2 months, while the highest mortality was indicated for men with a TTP of 10-17 months (HR = 1.31; 95% CI 0.98, 1.74). Among 53 799 hospitalizations, we found an increased hospitalization rate among women (HR = 1.21; 95% CI 1.0-1.41) and men (HR = 1.16; 95% CI 1.00-1.35) with a TTP of ≥18 months, and for men with a TTP of 2-9 months (HR = 1.14; 95% CI 1.01-1.30). A dose-response relationship was found for women regarding both mortality (P = 0.022) and hospitalizations (P = 0.018). Impaired fecundity was associated with a wide range of diseases and some causes of death, indicating a multi-factorial causal influence on fecundity, especially among women. LIMITATIONS, REASONS FOR CAUTION: A major limitation was that fecundity depends on both partners, which was not considered in this study. Moreover, we could not obtain information on a number of potential confounders. WIDER IMPLICATIONS OF THE FINDINGS: Fecundity seems positively correlated with overall health and may be a universal marker of future health and survival. These results add knowledge to the limited findings showing that reduced fecundity in women and poor semen quality in men may reflect worse health and a shorter life, particularly among women. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by NIH grant HD096468 (M.L.E., T.K.J. and R.L.J.). The authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Intrauterine testosterone exposure and depression risk in opposite-sex and same-sex twins, a Danish register study.

BACKGROUND: Males have a lower prevalence of depression than females and testosterone may be a contributing factor. A comparison of opposite-sex and same-sex twins can be used indirectly to establish the role of prenatal testosterone exposure and the risk of depression. We therefore aimed to explore differences in depression risk using opposite-sex and same-sex twins. METHODS: We included 126 087 opposite-sex and same-sex twins from the Danish Twin Registry followed in nationwide Danish registers. We compared sex-specific incidences of depression diagnosis and prescriptions of antidepressants between opposite-sex and same-sex twins using Cox proportional hazard regression. RESULTS: During follow-up, 2664 (2.1%) twins were diagnosed with depression and 19 514 (15.5%) twins had purchased at least one prescription of antidepressants. First, in male twins, we found that the opposite-sex male twins had the same risk of depression compared to the same-sex male twins {hazard ratio (HR) = 1.01 [95% confidence interval (CI) 0.88-1.17)]}. Revealing the risk of use of antidepressants, the opposite-sex male twins had a slightly higher risk of 4% (HR = 1.04 (95% CI 1.00-1.11)) compared with the same-sex male twins. Second, in the female opposite-sex twins, we revealed a slightly higher, however, not statistically significant risk of depression (HR = 1.08 (95% CI 0.97-1.29)) or purchase of antidepressants (HR = 1.01 (95% CI 0.96-1.05)) when compared to the same-sex female twins. CONCLUSIONS: We found limited support for the hypothesis that prenatal exposure to testosterone was associated with the risk of depression later in life.

Early ovarian ageing: is a low number of oocytes harvested in young women associated with an earlier and increased risk of age-related diseases?

STUDY QUESTION: Do young women with early ovarian ageing (EOA), defined as unexplained, and repeatedly few oocytes harvested in ART have an increased risk of age-related events? SUMMARY ANSWER: At follow-up, women with idiopathic EOA had an increased risk of age-related events compared to women with normal ovarian ageing (NOA). WHAT IS KNOWN ALREADY: Early and premature menopause is associated with an increased risk of cardiovascular diseases (CVDs), osteoporosis and death. In young women, repeated harvest of few oocytes in well-stimulated ART cycles is a likely predictor of advanced menopausal age and may thus serve as an early marker of accelerated general ageing. STUDY DESIGN, SIZE, DURATION: A register-based national, historical cohort study. Young women (≤37 years) having their first ART treatment in a public or private fertility clinic during the period 1995-2014 were divided into two groups depending on ovarian reserve status: EOA (n = 1222) and NOA (n = 16 385). Several national registers were applied to assess morbidity and mortality. PARTICIPANTS/MATERIALS, SETTING, METHODS: EOA was defined as ≤5 oocytes harvested in a minimum of two FSH-stimulated cycles and NOA as ≥8 oocytes in at least one cycle. Cases with known causes influencing the ovarian reserve (endometriosis, ovarian surgery, polycystic ovary syndrome, chemotherapy etc.) were excluded. To investigate for early signs of ageing, primary outcome was an overall risk of ageing-related events, defined as a diagnosis of either CVD, osteoporosis, type 2 diabetes, cancer, cataract, Alzheimer's or Parkinson's disease, by death of any-cause as well as a Charlson comorbidity index score of ≥1 or by registration of early retirement benefit. Cox regression models were used to assess the risk of these events. Exposure status was defined 1 year after the first ART cycle to assure reliable classification, and time-to-event was measured from that time point. MAIN RESULTS AND THE ROLE OF CHANCE: Median follow-up time from baseline to first event was 4.9 years (10/90 percentile 0.7/11.8) and 6.4 years (1.1/13.3) in the EOA and NOA group, respectively. Women with EOA had an increased risk of ageing-related events when compared to women with a normal oocyte yield (adjusted hazard ratio 1.24, 95% CI 1.08 to 1.43). Stratifying on categories, the EOA group had a significantly increased risk for CVD (1.44, 1.19 to 1.75) and osteoporosis (2.45, 1.59 to 3.90). Charlson comorbidity index (1.15, 0.93 to 1.41) and early retirement benefit (1.21, 0.80 to 1.83) was also increased, although not reaching statistical significance. LIMITATIONS, REASONS FOR CAUTION: Cycles never reaching oocyte aspiration were left out of account in the inclusion process and we may therefore have missed women with the most severe forms of EOA. We had no information on the total doses of gonadotrophin administered in each cycle. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that oocyte yield may serve as marker of later accelerated ageing when, unexpectedly, repeatedly few oocytes are harvested in young women. Counselling on life-style factors as a prophylactic effort against cardiovascular and other age-related diseases may be essential for this group of women. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The Hidradenitis Suppurativa Quality of Life (HiSQOL) score: development and validation of a measure for clinical trials.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory condition that can have a large negative impact on health-related quality of life (HRQOL). A reliable and validated measure of HS-specific HRQOL in clinical studies is needed. OBJECTIVES: To develop and validate the Hidradenitis Suppurativa Quality Of Life (HiSQOL©) scale, for clinical trial measurement of HS-specific HRQOL. METHODS: In stage 1, qualitative concept elicitation interviews were conducted with patients with HS in Denmark (n = 21) and the U.S.A. (n = 21). In stage 2, cognitive debriefing interviews were performed with U.S. (n = 30) and Danish patients with HS (n = 30). In stage 3 an observational study of 222 patients with HS in the U.S.A. was conducted for item reduction, measure validation and assessment of psychometric properties. In stage 4, an observational study of 215 patients with HS in Denmark was conducted to confirm the psychometric structure derived in stage 3. In both studies the Dermatology Life Quality Index, Hospital Anxiety and Depression Scale and numerical rating scale for pain were also included. RESULTS: In concept elicitation, 99 items were generated, which were reduced to 41 after removing duplicates. In cognitive debriefing, two items were added and one item removed. A 42-item instrument was psychometrically assessed. Based on psychometric analyses and patient input, the instrument was reduced to 17 items that had strong psychometric properties in both the U.S. and Danish samples. CONCLUSIONS: The HiSQOL is a reliable and valid instrument to measure HS-specific HRQOL in clinical trials.

Traumatic brain injury and risk of dementia at different levels of cognitive ability and education.

BACKGROUND AND PURPOSE: The effect of cognitive resources on the risk of dementia following traumatic brain injury (TBI) has hardly been investigated. The aim of this study was to examine the influence of cognitive ability and education in young adulthood on the association between TBI and dementia in men. METHOD: A cohort of 658 447 Danish men, born between 1939 and 1959, who had been cognitively assessed at conscription were followed in the Danish National Patient Registry and the National Prescription Registry from 1977 through 2016 for incident TBI and dementia. The association between TBI and dementia was analysed using Cox proportional regression. RESULTS: During follow-up, 29 781(4.5%) men experienced TBI and 10 971(1.7%) developed dementia. TBI was associated with a higher risk of subsequent dementia after adjustment for cognitive ability, education and psychiatric comorbidity. The risk estimate was higher for early-onset dementia (hazard ratio 5.49, 95% confidence interval 4.97-6.06) than for dementia diagnosed after age 60 years (hazard ratio 2.85, 95% confidence interval 2.63-3.10). The association was slightly stronger in men with the highest cognitive scores or education than amongst those at lower levels. CONCLUSION: Young adult cognitive ability did not explain a relatively strong association between TBI and dementia, and no evidence was found that cognitive ability or education was protective.

Validation and assessment of minimally clinically important difference of the unadjusted Health Assessment Questionnaire in a Danish cohort: uncovering ordinal bias.

Objectives: The Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) is a widely used patient-reported outcome for functional disability in rheumatoid arthritis (RA). Minimal clinically important differences (MCIDs) in the HAQ-DI were previously calculated based on device-corrected ordinal HAQ-DI scores, leading to limited generalizability and validity for today's patients. Our objectives were to examine the internal construct validity of the unadjusted HAQ-DI and to determine an MCID in a cohort of Danish RA patients based on the transformed linear logit scale of the HAQ-DI.Method: The study included 362 RA patients registered in the DANBIO registry. The Rasch model was fitted to HAQ-DI data at baseline and after 3 months' follow-up. MCID was calculated as the median changes in the original HAQ-DI score and logit HAQ-DI score in those patients who had experienced minimal improvement (15-30 mm on a 0-100 mm Patient Global scale).Results: HAQ-DI data showed acceptable fit to the Rasch model at both time-points, and consistent item ranking across time indicated instrument invariance. Sixty-one patients (16.8%, ~1/6) had an improvement above the MCID on the logit scale but improvement below the MCID on the original scale, while the opposite was not the case for any patients.Conclusions: The Danish unadjusted version of the HAQ-DI showed acceptable internal construct validity. Application of the logit MCID classified an additional one in six patients as having achieved an MCID compared to the MCID calculated on the ordinal scale, which may have potential implications for the powering of future studies.

Familial risk and heritability of depression by age at first diagnosis in Danish twins.

OBJECTIVE: Familial and genetic factors seem to contribute to the development of depression but whether this varies with age at diagnosis remains unclear. We examined the influence of familial factors on the risk of depression by age at first diagnosis. METHODS: We included 23 498 monozygotic and 39 540 same-sex dizygotic twins from the population-based Danish Twin Registry, followed from 1977 through 2011 in nationwide registers. We used time-to-event analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of first depression by age using monozygotic and same-sex dizygotic twin pairs. RESULTS: During follow-up, a total of 1545 twins were diagnosed with depression. For twins at age 35 or younger at first depression, heritability was estimated to be 24.8% (95% confidence interval [CI], 4.6-43.1%), whereas at age 90 it was 14.7% (95% CI, 3.1-26.3%). The relative recurrence risk was higher at younger ages: At age 35, the risk was 27.7-fold (95% CI, 20.0-35.5) and 6.9-fold (95% CI, 3.9-9.8) higher than the population risk for monozygotic and same-sex dizygotic twins, respectively, while the corresponding numbers were 3.0 (95% CI, 2.3-3.6) and 1.8 (95% CI, 1.3-2.2) at age 90. Heritability seemed similar for male and female twins. CONCLUSION: Familial risk of depression, caused either by genes or shared environment, seemed to slightly decrease with age at diagnosis and an elevated concordance risk for monozygotic over same-sex dizygotic pairs suggested a genetic contribution to the development of depression.

Carotenoid pigmentation in salmon: variation in expression at BCO2-l locus controls a key fitness trait affecting red coloration.

Carotenoids are primarily responsible for the characteristic red flesh coloration of salmon. Flesh coloration is an economically and evolutionarily significant trait that varies inter- and intra-specifically, yet the underlying genetic mechanism is unknown. Chinook salmon (Oncorhynchus tshawytscha) represents an ideal system to study carotenoid variation as, unlike other salmonids, they exhibit extreme differences in carotenoid utilization due to genetic polymorphisms. Here, we crossed populations of Chinook salmon with fixed differences in flesh coloration (red versus white) for a genome-wide association study to identify loci associated with pigmentation. Here, the beta-carotene oxygenase 2-like (BCO2-l) gene was significantly associated with flesh colour, with the most significant single nucleotide polymorphism explaining 66% of the variation in colour. BCO2 gene disruption is linked to carotenoid accumulation in other taxa, therefore we hypothesize that an ancestral mutation partially disrupting BCO2-l activity (i.e. hypomorphic mutation) allowed the deposition and accumulation of carotenoids within Salmonidae. Indeed, we found elevated transcript levels of BCO2-l in white Chinook salmon relative to red. The long-standing mystery of why salmon are red, while no other fishes are, is thus probably explained by a hypomorphic mutation in the proto-salmonid at the time of divergence of red-fleshed salmonid genera (approx. 30 Ma).

Incidence of medically treated depression in Denmark among individuals 15-44 years old: a comprehensive overview based on population registers.

OBJECTIVE: Examine the overall incidence of medically treated depression in Denmark among individuals 15-44 years old, and estimate the 5-year cumulative incidence of psychiatric hospital care among individuals treated first in non-hospital-based care. METHODS: We followed all individuals born in Denmark between 1969 and 1998 from age 15 or 2006 (whichever came first) until first depression treatment; death; emigration; or December 31, 2013. Incidence rates were estimated using Poisson regression. Cumulative incidence of hospital care following treatment in non-hospital care was estimated using Kaplan-Meier curves. RESULTS: In this sample of 2 014 760 individuals, incidence rates of depression in non-hospital and hospital-based care in 2012-2013 were 6.6 (95% Confidence Interval: 6.5-6.7) per 1000 person-years and 1.5 (95% CI: 1.5-1.6) per 1000 person-years, respectively. Overall, 85-90% of first medical treatment for depression took place outside of psychiatric hospitals, but a quarter (26.3%) of individuals treated for depression received hospital care initially or within 5 years. Incidence of hospital care was higher in women and younger individuals. CONCLUSIONS: Most medical treatment for depression in Denmark takes place in non-hospital settings. Women and younger individuals are more likely to receive hospital care both initially and within 5 years after first antidepressant treatment.