In recent years, evidence has accumulated with regard to the ubiquity of pleiotropy across the genome, and shared genetic etiology is thought to play a large role in the widespread comorbidity among ...psychiatric disorders and risk factors. Recent methods investigate pleiotropy by estimating genetic correlation from genome-wide association summary statistics. More comprehensive estimates can be derived from the known relatedness between genetic relatives. Analysis of extended twin pedigree data allows for the estimation of genetic correlation for additive and non-additive genetic effects, as well as a shared household effect. Here we conduct a series of bivariate genetic analyses in extended twin pedigree data on lifetime major depressive disorder (MDD) and three indicators of lifestyle, namely smoking behavior, physical inactivity, and obesity, decomposing phenotypic variance and covariance into genetic and environmental components. We analyze lifetime MDD and lifestyle data in a large multigenerational dataset of 19,496 individuals by variance component analysis in the 'Mendel' software. We find genetic correlations for MDD and smoking behavior (
= 0.249), physical inactivity (
= 0.161), body-mass index (
= 0.081), and obesity (
= 0.155), which were primarily driven by additive genetic effects. These outcomes provide evidence in favor of a shared genetic etiology between MDD and the lifestyle factors.
Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the ...disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting.
We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer.
We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality.
Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably.
The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we ...estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.
Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The ...more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.
A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common ...allergic diseases remain to be discovered, which could point to new therapeutic opportunities.
We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects.
We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study.
Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10−6. Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress TH2 responses.
Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
Summary
By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome‐wide association study ...(GWAS) comparing 403 unrelated nonagenarians from long‐living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta‐analysis of nonagenarian cases from the Rotterdam Study, Leiden 85‐plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P < 1 × 10−4) showed genome‐wide significance with survival into old age in the meta‐analysis of 4149 nonagenarian cases and 7582 younger controls OR = 0.71 (95% CI 0.65–0.77), P = 3.39 × 10−17. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE‐independent effect of rs2075650 on longevity, either in cross‐sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF‐1 in women (P = 0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found.
Lactic acid bacteria (LAB) are frequently encountered inhabitants of the human intestinal tract. A protective layer of mucus covers the epithelial cells of the intestine, offering an attachment site ...for these bacteria. In this study bioinformatics tools were used to identify and characterize proteins containing one type of mucus-binding domain, called MUB, that is postulated to play an important role in the adherence of LAB to this mucus layer. By searching in all protein databases 48 proteins containing at least one of these MUB domains in nine LAB species were identified. These MUB domains varied in size, ranging from approximately 100 to more than 200 residues per domain. Complete MUB domains were found exclusively in LAB. The number of MUB domains present in a single protein varied from 1 to 15. In some cases, orthologous proteins in closely related species contained a different number of domains, indicating that repeats of the domain undergo rapid duplication and deletion. Proteins containing the MUB domain were often encoded by gene clusters that encode multiple extracellular proteins. In addition to one or more copies of the MUB domain, many of these proteins contained other domains that are predicted to be involved in binding to and degradation of extracellular components. These findings strongly suggest that the MUB domain is an LAB-specific functional unit that performs its task in various domain contexts and could fulfil an important role in host-microbe interactions in the gastrointestinal tract.
By treating the coronavirus disease 2019 (COVID‐19) pandemic as a natural experiment, we examine the influence of substantial environmental change (i.e., lockdown measures) on individual differences ...in quality of life (QoL) in the Netherlands. We compare QoL scores before the pandemic (N = 25,772) to QoL scores during the pandemic (N = 17,222) in a sample of twins and their family members. On a 10‐point scale, we find a significant decrease in mean QoL from 7.73 (SD = 1.06) before the pandemic to 7.02 (SD = 1.36) during the pandemic (Cohen's d = 0.49). Additionally, variance decomposition shows an increase in unique environmental variance during the pandemic (0.30–1.08), and a decrease in the heritability estimate from 30.9% to 15.5%. We hypothesize that the increased environmental variance is the result of lockdown measures not impacting everybody equally. Whether these effects persist over longer periods and how they impact health inequalities remain topics for future investigation.
By treating the coronavirus disease 2019 (COVID‐19) pandemic as a natural experiment, we examine the influence of substantial environmental change (i.e., lockdown measures) on individual differences in quality of life (QoL) in the Netherlands. We compare QoL scores before the pandemic (N = 25,772) to QoL scores during the pandemic (N = 17,222) in a sample of twins and their family members. We find increased variance in QoL during the pandemic as the result of a large increase in unique environmental variance.
For the participants in the Netherlands Twin Register (NTR) we constructed the extended pedigrees which specify all relations among nuclear and larger twin families in the register. A total of ...253,015 subjects from 58,645 families were linked to each other, to the degree that we had information on the relations among participants. We describe the algorithm that was applied to construct the pedigrees. For > 30,000 adolescent and adult NTR participants data were available on harmonized neuroticism scores. We analyzed these data in the Mendel software package (Lange et al., Bioinformatics 29(12):1568–1570, 2013) to estimate the contributions of additive and non-additive genetic factors. In contrast to much of the earlier work based on twin data rather than on extended pedigrees, we could also estimate the contribution of shared household effects in the presence of non-additive genetic factors. The estimated broad-sense heritability of neuroticism was 47%, with almost equal contributions of additive and non-additive (dominance) genetic factors. A shared household effect explained 13% and unique environmental factors explained the remaining 40% of the variance in neuroticism.
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