Non-fatal disease burden for subtypes of depressive disorder: population-based epidemiological study

Background: Major depression is the leading cause of non-fatal disease burden. Because major depression is not a homogeneous condition, this study estimated the non-fatal disease burden for mild, moderate and severe depression in both single episode and recurrent depression. All estimates were assessed from an individual and a population perspective and presented as unadjusted, raw estimates and as estimates adjusted for comorbidity. Methods: We used data from the first wave of the second Netherlands-Mental-Health-Survey-and-Incidence-Study (NEMESIS-2, n = 6646; single episode Diagnostic and Statistical Manual (DSM)-IV depression, n = 115; recurrent depression, n = 246). Disease burden from an individual perspective was assessed as 'disability weight * time spent in depression' for each person in the dataset. From a population perspective it was assessed as 'disability weight * time spent in depression *number of people affected'. The presence of mental disorders was assessed with the Composite International Diagnostic Interview (CIDI) 3.0. Results: Single depressive episodes emerged as a key driver of disease burden from an individual perspective. From a population perspective, recurrent depressions emerged as a key driver. These findings remained unaltered after adjusting for comorbidity. Conclusions: The burden of disease differs between the subtype of depression and depends much on the choice of perspective. The distinction between an individual and a population perspective may help to avoid misunderstandings between policy makers and clinicians. © 2016 Biesheuvel-Leliefeld et al

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10−5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants—namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗—reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait

Body mass index and subsequent fracture risk: a meta-analysis to update FRAX®

The aim of this international meta-analysis was to quantify the predictive value of body mass index (BMI) for incident fracture and relationship of this risk with age, sex, follow-up time and bone mineral density (BMD). 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had femoral neck BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight:&amp;lt;18.5 kg/m2; Normal:18.5-24.9 kg/m2; Overweight:25.0-29.9 kg/m2; Obese I:30.0-34.9 kg/m2; Obese II:≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95%CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). HF risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26). Further adjustment for femoral neck BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, whilst overweight/obesity appeared protective base models, they became risk factors after additional adjustment for femoral neck BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX

Family history of fracture and fracture risk: a meta-analysis to update the FRAX® risk assessment tool

Summary In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. Purpose We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. Methods The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. Results As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23–1.52 and 1.19, 1.12–1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. Conclusions A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool

Site selection survey in Tabriz region for ICARDA - Iran research center

Survey report on site selection for the International Center for Agricultural Research in the Dry Areas in the Tabriz region of Iran. Discusses climate, soil types, water supply, vegetation, land tenure, communication, etc.; includes statistical data, bibliography