Aims/hypothesis Despite well-known sex differences in body composition it is not known whether sex-specific genetic or environmental effects contribute to these differences. Methods We assessed body ...composition in 2,506 individuals, from a young Dutch genetic isolate participating in the Erasmus Rucphen Family study, by dual-energy X-ray absorptiometry and anthropometry. We used variance decomposition procedures to partition variation of body composition into genetic and environmental components common to both sexes and to men and women separately and calculated the correlation between genetic components in men and women. Results After accounting for age, sex and inbreeding, heritability ranged from 0.39 for fat mass index to 0.84 for height. We found sex-specific genetic effects for fat percentage (fat%), lean mass, lean mass index (LMI) and fat distribution, but not for BMI and height. Genetic correlations between sexes were significantly different from 1 for fat%, lean mass, LMI, android fat, android:gynoid fat ratio and WHR, indicating that there are sex-specific genes contributing to variation of these traits. Genetic variance was significantly higher in women for the waist, hip and thigh circumference and WHR, implying that genes account for more variance of fat distribution in women than in men. Environmental variance was significantly higher in men for the android:gynoid fat ratio. Conclusions/interpretation Sex-specific genetic effects underlie sexual dimorphism in several body composition traits. The findings are relevant for studies on the relationship of body composition with common diseases like cardiovascular disease and type 2 diabetes and for genetic association studies.
Purpose
Percutaneous hepatic perfusion with melphalan (M-PHP) is a minimally invasive therapy with proven efficacy in patients with uveal melanoma (UM) liver metastases. M-PHP is associated with a ...short hospital admission time and limited systemic side effects. In this study, we assessed quality of life (QoL) in UM patients treated with M-PHP.
Materials and Methods
A prospective, single-center study including 24 patients treated with M-PHP for UM metastases to the liver. QoL questionnaires were collected at baseline, on day 2/3 after M-PHP, and on day 7 and day 21 after M-PHP, according to study protocol. The results were scored according to EORTC-QLQ C30 global health status (GHS), functional scales, and symptom scales. The difference in scores at baseline and subsequent time points was analyzed with the Wilcoxon signed-rank test and multiple testing Bonferroni correction. Adverse events (AE) were registered up to 30 days after M-PHP according to CTCAE v5.0.
Results
Twenty-four patients (14 males; median age 63.0 years) completed 96 questionnaires. Most scores on all scales declined on day 2/3 after M-PHP. On day 21 after M-PHP, 12 out of 15 scores returned to baseline, including median GHS scores. Three variables were significantly worse on day 21 compared to baseline: fatigue (6–33;
p
= 0.002), physical functioning (100 vs 86.7;
p
= 0.003), and role functioning (100 vs 66.7;
p
= 0.001). Grade 3/4 AEs consisted mainly of hematological complications, such as leukopenia and thrombopenia.
Conclusion
M-PHP causes fatigue and a decline in physical and role functioning in the 1st weeks after treatment, but GHS returns to baseline levels within 21 days.
Level of Evidence 3
Cohort study.
Graphical Abstract
Predicting human phenotypes from genotypes is a newly emerging field with relevance for personalized medicine 1 and forensics 2. However, only a few phenotypic traits can currently be identified from ...DNA information with accuracies sufficient for practical applications 1, most notably human eye (iris) color 3. It could be expected that individual age is too biologically complex to allow a simple and accurate molecular estimation from biological materials. Indeed, previously proposed genetic methods for human age estimation, based on the accumulation of mitochondrial DNA deletions or on telomere shortening, show low accuracies and various technical problems, and are therefore not suitable for practical applications 4. Proposed biochemical methods, such as those based on the accumulation of D-aspartic acid, involve the destructive analysis of specific body parts (such as bones, teeth and ligaments), and suffer from technical issues and bio-degradation 4. In the present study, we demonstrate that human individual age can be estimated accurately and reliably from blood using T-cell DNA rearrangements, and we provide a robust and sensitive real-time quantitative PCR protocol for application in various areas of bioscience.
Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic ...variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10
, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10
, β=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10
) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10
) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.
An international study of the epidemiologic characteristics of Creutzfeldt-Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, ...Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland.
Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes.
Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK.
This study has established overall epidemiologic characteristics for Creutzfeldt-Jakob disease (CJD) of all types in a multinational population-based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.
To investigate the co-occurrence of migraine and depression and assess whether shared genetic factors may underlie both diseases.
Subjects were 2,652 participants of the Erasmus Rucphen Family ...genetic isolate study. Migraine was diagnosed using a validated 3-stage screening method that included a telephone interview. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The contribution of shared genetic factors in migraine and depression was investigated by comparing heritability estimates for migraine with and without adjustment for symptoms of depression, and by comparing the heritability scores of depression between migraineurs and controls.
We identified 360 migraine cases: 209 had migraine without aura (MO) and 151 had migraine with aura (MA). Odds ratios for depression in patients with migraine were 1.29 (95% confidence interval CI 0.98-1.70) for MO and 1.70 (95% CI 1.28-2.24) for MA. Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96), and decreased after adjustment for symptoms of depression or use of antidepressant medication, in particular for MA. Comparison of the heritability scores for depression between patients with migraine and controls showed a genetic correlation between HADS-D score and MA.
There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors.
To determine the impact of oil-based versus water-based contrast on pregnancy and live birth rates ≤5 years after hysterosalpingography (HSG) in infertile women.
A 5-year follow-up study of a ...multicenter randomized trial.
Hospitals.
Infertile women with an ovulatory cycle, 18–39 years of age, and having a low risk of tubal pathology.
Use of oil-based versus water-based contrast during HSG.
Ongoing pregnancy, live births, time to ongoing pregnancy, second ongoing pregnancy.
A total of 1,119 women were randomly assigned to HSG with oil-based contrast (n = 557) or water-based contrast (n = 562). After 5 years, 444 of 555 women in the oil group (80.0%) and 419 of 559 women in the water group (75.0%) had an ongoing pregnancy (relative risk RR 1.07; 95% confidence interval CI 1.00–1.14), and 415 of 555 women in the oil group (74.8%) and 376 of 559 women in the water group (67.3%) had live births (RR 1.11; 95% CI 1.03–1.20). In the oil group, 228 pregnancies (41.1%) were conceived naturally versus 194 (34.7%) pregnancies in the water group (RR 1.18; 95% CI 1.02–1.38). The time to ongoing pregnancy was significantly shorter in the oil group versus the water group (10.0 vs. 13.7 months; hazard ratio, 1.25; 95% CI 1.09–1.43). No difference was found in the occurrence of a second ongoing pregnancy.
During a 5-year time frame, ongoing pregnancy and live birth rates are higher after tubal flushing with oil-based contrast during HSG compared with water-based contrast. More pregnancies are naturally conceived and time to ongoing pregnancy is shorter after HSG with oil-based contrast.
Netherlands Trial Register (NTR) 3270 and NTR6577(www.trialregister.nl).
Lavado de trompas con medio de contraste liposoluble o hidrosoluble en la histerosalpingografía por infertilidad: resultados reproductivos a largo plazo en un ensayo aleatorizado
Determinar el impacto del uso de contrastes liposolubles versus hidrosolubles sobre las tasas de embarazo y nacidos vivos ≤ 5 años post-histerosalpingografía (HSG) en mujeres infértiles.
Estudio de seguimiento a 5 años en un estudio multicéntrico aleatorizado.
Hopitalario.
Mujeres infértiles con ciclos ovulatorios, de edades entre 18 y 39 años y con bajo riesgo de patología tubárica.
Uso de contraste liposoluble versus hidrosoluble durante la HSG.
Embarazo en curso, nacidos vivos, tiempo hasta conseguir el embarazo, segundo embarazo en curso.
Se aleatorizaron un total de 1,119 mujeres asignándose a HSG con medio liposoluble (n=557) o hidrosoluble (n=562). Transcurridos 5 años, 444 de 555 mujeres en el grupo liposoluble (80%) y 419 de 559 en el grupo hidrosoluble (75%) consiguieron embarazo en curso (riesgo relativo RR 1.07; Intervalo de Confianza del 95% CI 1.00-1.14 y 415 de 555 mujeres en el grupo liposoluble (74.8%) y 376 de 559 mujeres en el grupo hidrosoluble (67.3%) tuvo nacidos vivos (RR 1.11; 95% CI 1.03-1.20). En el grupo hidrosoluble, 228 embarazos (41.1%) se concibieron espontáneamente vs 194 (34.7%) en el grupo hidrosoluble (RR 1.18; 95% CI 1.02-1.38). El tiempo para conseguir el embarazo fue significativamente menor en el grupo liposoluble versus el grupo hidrosoluble (10.0 vs 13.7 meses; hazard ratio 1.25; 95% CI 1.09-1.43). No se encontraron diferencias en la consecución de un segundo embarazo en curso.
En un periodo de 5 años, las tasas de embarazo en curso y nacidos vivos son mayores después del lavado tubárico con contraste liposoluble durante la HSG comparado con el lavado con contraste hidrosoluble. Un mayor número de embarazos se conciben espontáneamente y el tiempo para lograr un embarazo en curso es menor después de la HSG con contraste liposoluble.
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk ...genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To ...identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (
p
= 3.09 × 10
–15
) and the gene ontology (GO) terms for mtDNA metabolism (
p
= 1.43 × 10
–8
) and mtDNA replication (
p
= 1.2 × 10
–7
). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (
p
= 0.044) and non-cancer mortality (
p
= 6.56 × 10
–4
).
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