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Objective: Many psychiatric diseases have a strong familial aggregation, but it is unknown whether postpartum depression (PPD) without prior psychiatric history aggregates in families. Methods: Based on Danish national registers, we constructed a cohort with information on 848,544 singleton deliveries (1996–2017). Women with an episode of PPD were defined as having used antidepressant medication and/or had a hospital contact for depression within 6 months after delivery. Those with psychiatric history prior to the delivery were excluded. We estimated relative risk (RR) of PPD, comparing women with female relatives with and without PPD history, respectively. Results: Overall, women with a PPD history in female blood relatives had themselves a higher risk of PPD (RR = 1.64, 95% CI 1.16–2.34). Having the first-degree female relative with PPD history was associated with a more than 2.5 times (RR = 2.65, 95% CI 1.79–3.91) increased risk of PPD. However, having the second/third-degree female relative and/or a female non-blood relative with PPD history did not increase the woman's own risk of PPD (RR = 0.58, 95% CI 0.26–1.28, RR = 1.09, 95% CI 0.83–1.44). Conclusion: Postpartum depression aggregates in families with no other psychiatric history, but the findings do not support a strong genetic trait as a major cause. Other possible mechanisms are shared environment and/or health-seeking behavior in close relationships.

Background Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. Methods Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. Results We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. Conclusion This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease.

An online questionnaire based study, with the aim of investigating the link between autistic traits expressed at the family level and experiences of sibling bullying of 7-11 year old autistic children.

OBJECTIVES: Protein C (PC) deficiency is an inherited thrombophilia with a prevalence of 0.5% in the general population and 3% in subjects with a first-time deep vein thrombosis (DVT). Here we report a series of 14 PC-deficient Polish patients with comprehensive clinical and molecular characteristics, including long-term follow-up data and a deep mutational analysis of the PROC gene. PATIENTS AND METHODS: Fourteen unrelated probands (mean ± SD age 43.8 ± 13.0 years) with suspicion of PC deficiency, who experienced thromboembolic events and a majority of whom received anticoagulants (92.8%), were screened for PROC mutations by sequencing the nine PROC exons and their flanking intron regions. RESULTS: Ten probands (71.4%) had missense mutations, two patients (14.3%) carried nonsense variants, and the other two subjects (14.3%) had splice-site mutations, the latter including the c.401-1G>A variant, reported here for the very first time. The proband carrying the c.401-1A allele had a hepatic artery aneurysm with a highly positive family history of aneurysms and the absence of any mutations known to predispose to this vascular anomaly. CONCLUSION: A novel detrimental PROC mutation was identified in a family with aneurysms, which might suggest yet unclear links of thrombophilia to vascular anomalies, including aneurysms at atypical locations in women. The present case series also supports data indicating that novel oral anticoagulants (NOACs) are effective in PC deficient patients.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci. Electronic supplementary material The online version of this article (10.1007/s10048-020-00606-5) contains supplementary material, which is available to authorized users.

Presently, no data on the molecular basis of hereditary protein C (PC) deficiency in Spain is available. We analyzed the PC gene (PROC) in 109 patients with symptomatic PC deficiency and in 342 relatives by sequencing the 9 PROC exons and their flanking intron regions. In 93 probands, we found 58 different mutations (26 novel). Thirty-seven consisted of a nucleotide change, mainly missense mutations, 1 was a 6-nucleotide insertion causing the duplication of 2 amino acids, and 4 were deletions of 1, 3, 4, and 16 nucleotides. Nine mutations caused type II deficiencies, with the presence of normal antigen levels but reduced anticoagulant activity. Using a PC level of 70% as lowest normal limit, we found no mutations in 16 probands and 25 relatives with PC levels ≤ 70%. On the contrary, 4 probands and 12 relatives with PC levels > 70% carried the mutation identified in the proband. The spectrum of recurrent mutations in Spain is different from that found in the Netherlands, where the most frequent mutations were p.Gln174* and p.Arg272Cys, and is more similar to that found in France, where the most frequent were p.Arg220Gln and p.Pro210Leu. In our study, p.Val339Met (9 families), p.Tyr166Cys (7), p.Arg220Gln (6), and p.Glu58Lys (5) were the most prevalent. This study confirms the considerable heterogeneity of the genetic abnormality in PC deficiencies, and allowed genetic counseling to those individuals whose PC levels were close to the lower limit of the normal reference range.

BackgroundNumerous research studies have found an association between vitamin D (vitD) status and single-nucleotide polymorphisms (SNPs) in genes involved in vitD metabolism. It is notable that the influence of these SNPs on 25-hydroxyvitamin D [25(OH)D] levels might vary in different populations. In this study, we aimed to explore for genetic variants in genes related to vitD metabolism in families with vitD deficiency in Saudi Arabia using whole-exome sequencing (WES).MethodsThis family-based WES study was conducted for 21 families with vitD deficiency (n = 39) in Saudi Arabia. WES was performed for DNA samples, then resulting WES data was filtered and a number of variants were prioritized and validated by Sanger DNA sequencing.ResultsSeveral missense variants in vitD-related genes were detected in families. We determined two variants in low-density lipoprotein 2 gene (LRP2) with one variant (rs2075252) observed in six individuals, while the other LRP2 variant (rs4667591) was detected in 13 subjects. Single variants in 7-dehydrocholesterol reductase (DHCR7) (rs143587828) and melanocortin-1 receptor (MC1R) (rs1805005) genes were observed in two subjects from two different families. Other variants in group-specific component (GC), cubilin (CUBN), and calcium-sensing receptor (CASR) gene were found in index cases and controls. Polymorphisms in GC (rs9016) and CASR (rs1801726) were found in the majority of family cases (94 and 88%), respectively.ConclusionIn vitD-deficient families in Saudi Arabia, we were able to detect a number of missense exonic variants including variants in GC (rs9016), CUBN (rs1801222), CASR (rs1801726), and LRP2 (rs4667591). However, the existence of these variants was not different between affected family members and non-affected controls. Additionally, we were able to find a mutation in DHCR7 (rs143587828) and a polymorphism in LRP2 (rs2075252), which may affect vitD levels and influence vitD status. Further studies are now required to confirm the association of these variants with vitD deficiency.

Background: Social anxiety disorder (SAD) is a serious psychiatric condition with a high prevalence, and a typical onset during childhood/adolescence. The condition runs in families, but it is largely unknown which neurobiological characteristics transfer this genetic vulnerability (‘endophenotypes’). Using data from the Leiden Family Lab study on SAD, including two generations of families genetically enriched for SAD, we investigated whether social anxiety (SA) co-segregated with changes in intrinsic functional connectivity (iFC), and examined heritability. Methods: Functional MRI data were acquired during resting-state in 109 individuals (56 males; mean age: 31·5, range 9·2-61·5 years). FSL's tool MELODIC was used to perform independent component analysis. Six networks of interest (default mode, dorsal attention, executive control, frontoparietal, limbic and salience) were identified at the group-level and used to generate subject-specific spatial maps. Voxel-wise regression models, with SA-level as predictor and voxel-wise iFC as candidate endophenotypes, were performed to investigate the association with SA, within masks of the networks of interest. Subsequently, heritability was estimated. Findings: SA co-segregated with iFC within the dorsal attention network (positive association in left middle frontal gyrus and right postcentral gyrus) and frontoparietal network (positive association within left middle temporal gyrus) (cluster-forming-threshold z>2·3, cluster-corrected extent-threshold p

[Background] Substantial evidence supports the existence of neurocognitive endophenotypes in bipolar disorder (BD), but very few longitudinal studies have included unaffected relatives. In a 5-year, follow-up, family study, we have recently suggested that deficits in manual motor speed and visual memory could be endophenotype candidates for BD. We aimed to explore whether this also applies to processing speed., [Methods] A sample of 348 individuals, including 163 BD patients, 65 unaffected first-degree relatives (BD-Rel) and 120 genetically unrelated healthy controls (HC), was assessed with the Digit Symbol Substitution Test (DSST) on two occasions over a 2-year period (T1, T2). DSST values were controlled for age, years of education, occupational status, and subsyndromic mood symptoms. Differences between groups were evaluated with ANCOVAs., [Results] At T1 BD performed significantly worse than HC (p < 0.001; Cohen's d = 1.38) and BD-Rel (p < 0.001; Cohen's d = 0.82). BD-Rel showed an intermediate performance with significant differences with HC (p < 0.01; Cohen's d = 0.50). Similarly, at T2 BD performed significantly worse than HC (p < 0.001; Cohen's d = 1.44) and BD-Rel (p < 0.01; Cohen's d = 0.51). BD-Rel performance was intermediate and significantly lower than that of HC (p < 0.01; Cohen's d = 0.97). A Repeated Measures ANOVA revealed no significant between-group differences in performance over time (p > 0.05)., [Conclusions] The results of this longitudinal, family study suggest that impaired processing speed may represent a suitable cognitive endophenotype for BD. Further research on the field is required to confirm these preliminary findings., Dr Vicent Balanzá-Martínez acknowledges the support from Instituto de Salud Carlos III (PI16/1770, PROBILIFE Study).

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis. Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases. This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

BACKGROUND: Patients with social anxiety disorder (SAD) fear negative evaluation in social situations. Specifically, previous work indicated that social anxiety is associated with increased medial prefrontal cortex activation in response to unintentional social norm (SN) transgressions, accompanied by increased embarrassment ratings for such SN violations. Here, we used data from the multiplex, multigenerational LFLSAD (Leiden Family Lab study on Social Anxiety Disorder), which involved two generations of families genetically enriched for SAD, and investigated whether these neurobiological and behavioral correlates of unintentional SN processing are SAD endophenotypes. Of four endophenotype criteria, we examined two: first, the cosegregation of these characteristics with social anxiety (SA) within families of SAD probands (criterion 4), and second, the heritability of the candidate endophenotypes (criterion 3).METHODS: Participants (n = 110, age range 9.0-61.5 years, eight families) performed the revised Social Norm Processing Task; functional magnetic resonance imaging data and behavioral ratings related to this paradigm were used to examine whether brain activation in response to processing unintentional SN violations and ratings of embarrassment were associated with SA levels. Next, heritability of these measurements was estimated.RESULTS: As expected, voxelwise functional magnetic resonance imaging analyses revealed positive associations between SA levels and brain activation in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, and these brain activation levels displayed moderate to moderately high heritability. Furthermore, although SA levels correlated positively with behavioral ratings of embarrassment for SN transgressions, these behavioral characteristics were not heritable.CONCLUSIONS: These results show, for the first time, that brain responses in the medial prefrontal cortex and medial temporal gyrus, superior temporal gyrus, and superior temporal sulcus, related to processing unintentional SN violations, provide a neurobiological candidate endophenotype of SAD.

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders., Male to female sex ratio of psychiatric disorders, sorted from most to least prevalent among females.

Background Previous studies found that Ser9Gly (rs6280) might be involved in the occurrence of schizophrenia. However, no consist conclusion has yet been achieved. Compared to the case-control study, the family-based study took into account stratification bias. Thus, we conducted a meta-analysis of family-based studies to measure a pooled effect size of the association between Ser9Gly and the risk of schizophrenia. Methods The relevant family-based studies were screened using the electronic databases by the inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the correction between Ser9Gly polymorphism and schizophrenia susceptibility. Subgroup analysis was performed by stratification of ethnicity (i.e., East Asian, Caucasian, and other populations). Additionally, publication bias was evaluated by the funnel plot. Results After literature searching, a total of 13 family-based association studies were included, which contained 11 transmission disequilibrium test (TDT) studies with 1219 informative meiosis and 5 haplotype-based haplotype relative risk (HRR) studies. No statistical significance of the heterogeneity was detected in TDT and HRR studies. Thus, the pooled effect size was calculated under the fixed effect model. The results found that the association was significantly protective in East Asian in TDT studies (204 informative meiosis, OR = 0.744, 95% CI = 0.564–0.980, Z-value = − 2.104, p = 0.035). Conclusions The meta-analysis based on the family study found a protective association of Ser9Gly in East Asian. In future, large sample molecular epidemiology studies are needed to validate our findings.

Background The association between resting heart rate (HR) and cardiovascular outcomes, especially heart failure, is now well established. However, whether HR is mainly an integrated marker of risk associated with other features, or rather a genetic origin risk marker, is still a matter for debate. Previous studies reported a heritability ranging from 14% to 65%. Design We assessed HR heritability in the STANISLAS family-study, based on the data of four visits performed over a 20-year period, and adjusted for most known confounding effects. Methods These analyses were conducted using a linear mixed model, adjusted on age, sex, tea or coffee consumption, beta-blocker use, physical activity, tobacco use, and alcohol consumption to estimate the variance captured by additive genetic effects, via average information restricted maximum likelihood analysis, with both self-reported pedigree and genetic relatedness matrix (GRM) calculated from genome-wide association study data. Results Based on the data of all visits, the HR heritability (h2) estimate was 23.2% with GRM and 24.5% with pedigree. However, we found a large heterogeneity of HR heritability estimations when restricting the analysis to each of the four visits (h2 from 19% to 39% using pedigree, and from 14% to 32% using GRM). Moreover, only a little part of variance was explained by the common household effect ( Conclusion Using a comprehensive analysis based on a family cohort, including the data of multiple visits and GRM, we found that HR variability is about 25% from genetic origin, 25% from repeated measures and 50% remains unexplained.

BackgroundCauses of the comorbidity of substance misuse with anxiety-related and depressive disorders (anxiety/depression) remain poorly known. We estimated associations of substance misuse and anxiety/depression in the general population and tested them while accounting for genetic and shared environmental factors.MethodsWe studied individuals born in Sweden 1968–1997 (n = 2 996 398) with follow-up in nationwide register data for 1997–2013. To account for familial effects, stratified analyses were conducted within siblings and twin pairs. Substance misuse was defined as ICD-10 alcohol or drug use disorder or an alcohol/drug-related criminal conviction. Three dimensions of ICD-10 anxiety and depressive disorders and a substance misuse dimension were identified through exploratory factor analysis.ResultsSubstance misuse was associated with a 4.5-fold (95% CI 4.50–4.58) elevated risk of lifetime generalized anxiety/depression, 4.7-fold (95% CI 4.63–4.82) elevated risk of panic disorder and agora/social phobia, and 2.9-fold elevated risk of phobias/OCD (95% CI 2.82–3.02) as compared to those without substance misuse. The associations were attenuated in within-family analyses but we found elevated risks in monozygotic twin pairs discordant for substance misuse as well as significant non-shared environmental correlations. The association between anxiety/depression and substance misuse was mainly driven by generalized anxiety/depression, whereas other anxiety/depression dimensions had minor or no independent associations with substance misuse.ConclusionsSubstance misuse and anxiety/depression are associated at the population level, and these associations are partially explained by familial liabilities. Our findings indicate a common genetic etiology but are also compatible with a potential partially causal relationship between substance misuse and anxiety/depression.

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low‐density lipoprotein cholesterol ( LDL ‐C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population‐based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first‐degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL ‐C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta‐analysis of the hyperlipidemic families and the population cohort (high LDL ‐C: hazard ratio, 1.74 [95% CI, 1.48–2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09–1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid‐lowering medication. In lipidomic profiling, high LDL ‐C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P ‐value range 0.038–2.3×10 −56 ). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL ‐C: r =0.80; triacylglycerides: r =0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population‐based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL ‐C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population‐ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

The heart of the obsessional process may be considered the subject's underlying impression that “something is wrong” or “that something is not just as it should be”. This phenomenon, labeled “not just right experiences” (NJREs), has increasingly been receiving attention as a possible marker of obsessive-compulsive disorder (OCD). The present study sought to add to the evidence that NJREs may be a putative endophenotype of obsessional symptoms. To this aim, measures of NJREs, obsessive-compulsive (OC) symptoms and psychological distress were compared in offspring of parents with and without OC symptoms. The offspring of parents with OC symptoms (N=120) reported higher frequency and severity of NJREs compared to offspring of parents without OC symptoms (N=106). Such differences remained significant for NJREs frequency and close to significance for NJREs severity, when general distress (i.e., anxiety and depression) was controlled. The possible role of NJREs as an endophenotype for OCD is discussed in reference to Gottesman and Gould criteria and the National Institute of Mental Health RDoC initiative.

Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology. To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes. In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree. From the analysis of the pedigree, we were able to identify a “protective” haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model.

A case-control family study is a study where individuals with a disease of interest (case probands) and individuals without the disease (control probands) are randomly sampled from a well-defined population. Possibly right-censored age at onset and disease status are observed for both probands and their relatives. Correlation among the outcomes within a family is induced by factors such as inherited genetic susceptibility, shared environment, and common behavior patterns. For this setting, we present a nonparametric estimator of the marginal survival function, based on local linear estimation of conditional survival functions. Asymptotic theory for the estimator is provided, making this paper the first to present for this data setting a fully nonparametric estimator with proven consistency. Simulation results are presented showing that the method performs well. The method is illustrated on data from a prostate cancer study.

Presently, no data on the molecular basis of hereditary protein C (PC) deficiency in Spain is available. We analyzed the PC gene ( PROC ) in 109 patients with symptomatic PC deficiency and in 342 relatives by sequencing the 9 PROC exons and their flanking intron regions. In 93 probands, we found 58 different mutations (26 novel). Thirty-seven consisted of a nucleotide change, mainly missense mutations, 1 was a 6-nucleotide insertion causing the duplication of 2 amino acids, and 4 were deletions of 1, 3, 4, and 16 nucleotides. Nine mutations caused type II deficiencies, with the presence of normal antigen levels but reduced anticoagulant activity. Using a PC level of 70% as lowest normal limit, we found no mutations in 16 probands and 25 relatives with PC levels 70% carried the mutation identified in the proband. The spectrum of recurrent mutations in Spain is different from that found in the Netherlands, where the most frequent mutations were p.Gln174* and p.Arg272Cys, and is more similar to that found in France, where the most frequent were p.Arg220Gln and p.Pro210Leu. In our study, p.Val339Met (9 families), p.Tyr166Cys (7), p.Arg220Gln (6), and p.Glu58Lys (5) were the most prevalent. This study confirms the considerable heterogeneity of the genetic abnormality in PC deficiencies, and allowed genetic counseling to those individuals whose PC levels were close to the lower limit of the normal reference range.

Background The influence of familial factors on the prognosis of heart failure ( HF ) is unknown. This nationwide follow‐up study aimed to determine familial mortality risks of HF among Swedish siblings hospitalized for HF . Methods and Results We linked several Swedish nationwide registers for individuals aged 0 to 80 years. The study population consisted of 373 people hospitalized for HF for the first time between 2000 and 2012 with 1 proband sibling previously hospitalized for HF for the first time between 2000 and 2007. Families with congenital heart disease were excluded. Familial hazard ratios ( HR s) for mortality after first HF hospitalization were determined with Cox regression. The influence of proband survival was categorized as short survival (HF comorbidities. Short proband survival was associated with a HR of 2.02 (95% confidence interval, 1.32–3.09) for overall mortality. This HR was 2.35 (95% confidence interval, 1.18–4.67) in patients without preceding coronary heart disease, whereas patients with ischemic HF had an HR of 1.84 (95% confidence interval, 1.05–3.23). For each year of proband survival, the risk of death decreased, with a HR of 0.86 (95% confidence interval, 0.77–0.98). Conclusions Our results suggest that family history of poor survival in specific relation to HF is an important risk factor for death in HF patients. Additional studies are needed to characterize the molecular underpinnings and detailed phenotypic characteristics of such patients.

IntroductionEarly-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology. Implicated genes encode proteins involved in brain development, synapses morphology and plasticity and neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS and ASD, underlying the neurodevelopmental hypothesis of EOS.The main objective of our study is to identify disease-causing genetic mutations in a cohort of patients affected by both EOS and ASD. Special attention will be paid to genes involved in neurodevelopmental pathways.Methods and analysisWe describe a multicentric study in a paediatric population. The study started in April 2014. Inclusion criteria are: age 7–22 years, diagnosis of EOS with comorbid ASD and IQ >50; Parents and siblings are also enrolled. We perform psychiatric assessments (Mini International Neuropsychiatric Interview, Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime Version, Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms) together with neurocognitive evaluations (IQ, Trail Making Test A/B and verbal fluency). Then, we study variants of the coding part of DNA (exome), using next-generation sequencing process on trio (mother, father and child). Bioinformatics tools (RVIS and PolyPhen-2) are used to prioritise disease-causing mutations in candidate genes. The inclusion period will end in November 2019.Ethics and disseminationThe study protocol was approved by the Local Ethic Committee and by the French National Agency for Medicines and Health Products Safety. All patients signed informed consent on enrolment in the study. Results of the present study should help to unravel the molecular pathology of EOS, paving the way for an early therapeutic intervention.Trial registration numberNCT0256552

Questioning is a core component of formal pedagogy. Parents commonly question children, but do they use questions to teach? This article defines "pedagogical questions" as questions for which the questioner already knows the answer and intended to help the questionee learn. Transcripts of parent-child conversations were collected from the CHILDES database to examine the frequency and distribution of pedagogical questions. Analysis of 2,166 questions from 166 mother-child dyads and 64 father-child dyads (child's age between 2 and 6 years) showed that pedagogical questions are commonplace during day���to���day parent-child conversations and vary based on child's age, family environment, and historical era. The results serve as a first step toward understanding the role of parent-child questions in facilitating children's learning.

The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA‐A, 29 HLA‐C, 75 HLA‐B, and 42 HLA‐DRB1 alleles were identified. In the HLA haplotypes of A‐C‐B‐DRB1 and C‐B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies.

The use of best linear unbiased prediction/restricted maximum likelihood (BLUP/REML) in perennial crops and animal breeding enhances selection gain. However, its advantage with respect to annual crops is not clear. We compared the BLUP and best linear unbiased estimator selection efficiency in the breeding of various potato generations. This was done by simulating various selection intensities on clonal families (full sibs), and clones. The characters evaluated were tuber yield and tuber specific gravity. Two criteria were adopted for comparison: a) incidence of families or clones and b) selection gain. For tuber yield, BLUP/REML method was slightly more efficient for selecting families in the first clonal generation, if it were above 50%. Below this value, both methods were equivalent. However, they both presented equal behavior for family selection of tuber specific gravity. For clonal selection, BLUP/REML showed robust superiority from 10 to 90% selection intensities in both characters. Therefore, the adequate use of BLUP/REML in potato breeding can enhance the selection gain on the yield and specific gravity of tubers. © FUNPEC-RP.

BACKGROUND: With China's rapid economic growth in the past few decades, there is currently an emerging focus on happiness. Cross-cultural validity studies have indicated that the four-item Subjective Happiness Scale (SHS) has high internal consistency and stable reliability. However, the psychometric characteristics of the SHS in broader Chinese community samples are unknown. PURPOSE: We evaluated the factor structure and psychometric properties of the SHS in the Hong Kong general population. METHODS: The Chinese SHS was derived using forward-backward translation. Of the Cantonese-speaking participants aged >/=15 years, 2,635 were randomly selected from the random sample component of the FAMILY Cohort, a territory-wide cohort study in Hong Kong. In addition to the SHS, a single-item overall happiness scale, the Patient Health Questionnaire-9 (PHQ-9), the Family Adaptation, Partnership, Growth, Affection, Resolve (APGAR) scale, and the Medical Outcomes Study 12-item short-form version 2 (SF-12) mental and physical health scales were administered. RESULTS: Exploratory and confirmatory factor analyses supported a single factor with high loadings for the four SHS items. Multiple group analyses indicated factor invariance across sex and age groups. Cronbach's alpha was 0.82, and 2-week test-retest reliability (n = 191) was 0.70. The SHS correlated significantly with single-item overall happiness (Spearman's rho [rho] = 0.57), Family APGAR (rho = 0.26), PHQ-9 (rho = -0.34), and mental health-related quality of life (rho = 0.40) but showed a lower correlation with physical health (rho = 0.15). A regression model that included the PHQ-9 and Family APGAR scores explained 37 % of the variance in SF-12 mental health scores; adding the SHS raised the variance explained to 41 %. CONCLUSIONS: Our results support the reliability and validity of the SHS as a relevant component in the measurement battery for mental well-being in a Chinese general population., published_or_final_version

Background Autosomal recessive Long QT syndrome is characterized by prolonged QTc along with congenital bilateral deafness depends on mutations in K + channel genes. A family of a Long QT syndrome proband from India has been identified with novel indel variations. Methods The molecular study of the proband revealed 4 novel indel variations in KCNQ1 . In-silico analysis revealed the intronic variations has led to a change in the secondary structure of mRNA and splice site variations. The exonic variations leads to frameshift mutations. DNA analysis of the available family members revealed a carrier status. Results and Conclusion It is thus predicted that the variations may lead to a change in the position of the splicing enhancer/inhibitor in KCNQ1 leading to the formation of a truncated S2–S3 fragment of KCNQ1 transmembrane protein in cardiac cells as well as epithelial cells of inner ear leading to deafness and aberrant repolarization causing prolonged QTc.

This article intends to emphasize the evolution of processes and phenomena in the national economy, with adverse effects on the lives of the vast majority of people and the way this evolution impacts the people's quality of life. The necessity and significance of the topic are also linked to the fact that along with developing a market economy, the quality of life (as a social-economic category) is an indicator of the “social price” of changes that were prevalent in the daily life of Romania during the period of great transformations in the society.The paper presents the partial results of a complex research study conducted in Jiu Valley and it refers to its resident's quality of life. The quality of life diagnosis contains the necessary family study that posits that the quality of the family life influences strongly the individual's quality of life. In reference to the family, within the framework of integral research of the quality of life, as a social subsystem, in interdependence with other subsystems and also with the entire social system, we will perceive the relationship between this dimension and other dimensions of the quality of life. We will also consider the dependence between the society performance, as a whole and the adequate functionality of the family group.The complexity of the investigation of subjects involved the use of several research methods that are focused-group, sociological inquiry based on questionnaires and unstructured observation.The large majority of the investigated subjects are satisfied with their family life, emphasizing once again the central part of the family in people's lives.

Background: Few studies have examined Manual Motor Speed (MMS) in bipolar disorder (BD). The aim of this longitudinal, family study was to explore whether dysfunctional MMS represents a neurocognitive endophenotype of BD. Methods: A sample of 291 subjects, including 131 BD patients, 77 healthy first-degree relatives (BD-Rel), and 83 genetically-unrelated healthy controls (HC), was assessed with the Finger-Tapping Test (En) on three occasions over a 5-year period. Dependence of FTT on participants' age was removed by means of a lineal model of HC samples, while correcting simultaneously the time and learning effect. Differences between groups were evaluated with an ANOVA test. Results: The patients' performance was significantly worse than that of HC over time (p = 0.057). Performance of the BD-Rel group was intermediate to that of BD and HC. Most sociodemographic and clinical variables did not affect these results in patients. (p >= 0.1). However, treatment with carbamazepine and benzodiazepines may exert a iatrogenic effect on MMS performance (p

Childhood-onset schizophrenia (COS) refers to schizophrenia with onset of psychotic symptoms prior to a child's 13th birthday. Optimal treatment likely includes family-based services supplementing antipsychotic pharmacotherapy. However, family-based services can require adjustment based on parental psychopathology; there has been little literature exploring the frequency or type of psychopathology seen in parents of COS cases. This report includes the results of a structured psychiatric evaluation on 80 parents of a COS case with comparison to a sample of 304 parents. Having a child with psychosis and being of minority racial/ethnicity status increased risk for psychiatric illness. Psychotic disorders (15% vs. 5%), mood disorders (54% vs. 27%), anxiety disorders (30% vs. 18%), and substance use disorders (49% vs. 31%) were all increased in the parents with a psychotic child. Psychiatric illness is common in parents of a child with COS and will need to be considered as family-based services for COS are developed.

Obsessive-compulsive disorder (OCD) has been seen to run in families and genetics help to understand its heritability. In this review, we summarize older studies which focused on establishing the familial nature of OCD, including its various dimensions of symptoms, and we focus on recent findings from studies using both the candidate gene approach and genome-wide association study (GWAS) approach. The family studies and twin studies establish the heritability of OCD. Candidate gene approaches have implicated genes in the serotonergic, glutamatergic, and dopaminergic pathways. GWAS has not produced significant results possibly due to the small sample size. Newer techniques such as gene expression studies in brain tissue, stem cell technology, and epigenetic studies may shed more light on the complex genetic basis of OCD.

The aim of the study was to determine the relative influence of heredity and environment on peak bone density and also to estimate the risk of having low peak bone density if the bone density of parents is low. The study comprised 83 families (48 daughters and 35 sons and their parents). The children were at an age when bone density is at its peak at most skeletal sites (22.2+/-1.8 girls; 23.1+/-1.2 boys). Bone mineral density (BMD; g/cm(2)) was determined by dual-energy X-ray absorptiometry. Anthropometric measurements were made, and calcium intake and physical activity were assessed. Heredity accounted for 22-42% of the variation in BMD of the children, depending on the skeletal site. Heritability for cortical BMD of mid-radius was considerably lower than that for spinal trabecular BMD. Children whose parents had low BMDs (T-score< or =-1) were 1.1 times more likely to inherit low BMD. Child BMD depended significantly on parent BMD and also on physical activity. In our study, heredity accounted for the total BMD variation more than the environmental factors. This influence was lower in the cortical than in the trabecular parts of the skeleton. Optimal environmental factors, such as physical activity, may influence the risk of inheriting low BMD.

Obsessive-compulsive disorder (OCD) is a serious psychiatric disorder that affects approximately 2% of the populations of children and adults. Family aggregation studies have demonstrated that OCD is familial, and results from twin studies demonstrate that the familiality is due in part to genetic factors. Only three genome-wide linkage studies have been completed to date, with suggestive but not definitive results. In addition, over 80 candidate gene studies have been published. Most of these studies have focused on genes in the serotonergic and dopaminergic pathways. Unfortunately, none have achieved genome-wide significance, and, with the exception of the glutamate transporter gene, none have been replicated. Future research will require the collaboration of multidisciplinary teams of investigators to (i) achieve sufficiently large samples of individuals with OCD; (ii) apply the state-of-the-art laboratory techniques; and ( iii) perform the bioinformatic analyses essential to the identification of risk loci.

Contains fulltext : 80084.pdf (Publisher’s version ) (Closed access) Psoriasis is a common inflammatory skin disease with a prevalence of 2-3% in individuals of European ancestry. In a genome-wide search for copy number variants (CNV) using a sample pooling approach, we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster. The absence of LCE3B and LCE3C (LCE3C_LCE3B-del) is significantly associated (P = 1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the United States, and in a family-based study (P = 5.4E-04). LCE3C_LCE3B-del is tagged by rs4112788 (r(2) = 0.93), which is also strongly associated with psoriasis (P < 6.6E-09). LCE3C_LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility.

The aim of this study was to explore the aetiology of individual differences in manipulation tactics and the relationship between manipulation tactics and personality traits using a family study design. The sample used in the study consisted of 193 (60 male, 133 female) pupils of high-schools in Zagreb and their parents (152 male, 188 female). All participants completed a new instrument assessing manipulation tactics, as well as the NEO-Five Factor Inventory (NEO-FFI) to assess personality. Data were collected so that both self-reports and observer-reports of manipulation tactics and personality traits were available. Two measures of parent–child similarity in manipulation tactics were calculated: correlations between single parent and offspring, and midparent–offspring regressions. Both measures indicate that there is a familial aggregation of manipulation tactics. The relationship between personality traits and manipulation tactics was tested in correlation and regression analyses. Although both analyses showed coherent links between personality traits and manipulation tactics (e.g. low Agreeableness and high Neuroticism were associated with higher use of manipulation tactics), results also indicate that personality traits play a marginal role in selection and use of manipulation tactics.

Previous behaviour genetic studies of sensation seeking are suggesting substantional heritability estimates of this trait, ranging between 50-60%. However, the majority of these studies was done using twin design. The study reported here used a family design, and the sample consisted of highschool students and their parents: 151 offspring (95 females and 56 males), 148 mothers and 118 fathers. Both offspring and their parents completed Sensation Seeking Scale - Form V (SSS-V). Beside SSS-V, parents also completed the Parental Behaviour Scale (PBS). Parental Behaviour Scale is a measure of parental behaviour developed for the purpose of this research. It consists of 10 items measuring two dimensions of parental behaviour: parental affection and parental control. Each parent had to report his/her own behaviour, as well as the behaviour of their partners. Parents' SSS-V and PBS scores were related with the offspring's SSS-V scores. Father-offspring correlations ranged between 0.18 and 0.27 for different sensation-seeking subscales (Thrill and Adventure Seeking Scale - TAS ; Experience Seeking Scale - ES ; Disinhibition Scale - Dis ; Boredom Susceptibility Scale - BS), while mother-offspring correlations ranged between 0.02 and 0.24. Regressions of offspring on midparent scores ranged between 0.18 and 0.31. Mother-father correlations were statistically significant for all subscales, except for TAS subscale, and ranged between 0.26 and 0.46 suggesting assortative mating for sensation seeking in this sample. The only measure from Parental Behaviour Scale that correlated with children's sensation seeking was fathers' parental control (average fathers' control correlated 0.24 with total children's SSS score).

Tez (Yüksek Lisans) -- İstanbul Teknik Üniversitesi, Fen Bilimleri Enstitüsü, 2015, Thesis (M.Sc.) -- İstanbul Technical University, Institute of Science and Technology, 2015, Behçet Sendromu, vücuttaki birçok doku ve sistemin iltihaplı tutulumuyla öne çıkan, kronik romatolojik bir hastalıktır. Başlıca belirtileri ağızda ve cinsel organda sıklıkla tekrar eden yaralar, vücutta sivilceler ve kızarıklıklardır. Bununla beraber, eklemlerde, dolaşım sisteminde, merkezi sinir sisteminde, gözün görme tabakasında, sindirim sistemininde ve akciğer, böbrek gibi organlarda iltihaplanma görülmektedir. Hastalık genellikle daha ağır bir seyirle 20’li ve 30’lu yaşlarda başlar. Behçet Sendromu’na, İpek Yolu olarak tanımlanan, Akdeniz ve Orta Doğu popülasyonlarının da üzerinde bulunduğu güzergahta sık rastlanmaktadır. Türkiye’de ise hastalığın sıklığının, 100.000’ de 20 ile 420 arasında değiştiği gösterilmiştir. Hastalık etkenleri, ailesel birikim ve Behçet Sendromlu ailelerde artan HLA-B51 sıklığı gibi indikasyonlar ile birlikte enfeksiyonel ajanlar, çevresel faktörler ve henüz tanımlanmamış immünolojik mekanizmalar olarak öne sürülmüştür. Bunların içinde HLA-B geninin bir alt aleli olan HLA-B51 aleli, bugüne kadar Behçet Sendromu ile ilişkilendirilmiş en önemli işaretlerden biridir. HLA-B geni 6. Kromozomun p(kısa) kolunda 21.3 ile tanımlanan bölgesinde bulunmaktadır.HLA-B, insan lökosit antijeni (HLA) denilen kompleks grubun başlıca genlerindendir. Görevi bağışıklık siteminde T hücrelerine antijen tanıtımını sağlamaktır. HLA-B geninin birden çok aleli bulunmaktadır. Bu alellerden Behçet Sendromu ile bağlantısı bilinen aleller HLA-B51, HLA-B15, HLA-B27 ve HLA-B57 olarak gösterilmiştir. Fakat bunların içinden HLA-B51 aleli günümüze kadar yapılan çalışmalarda, hastalık ile en çok bağlantılı bulunan alel olmuştur. HLA-B51 alelinin 89 dan fazla alt tip aleli bulunmaktadır. Günümüzde, HLA-B 51 alelinin HLA-B5101 ve HLA-B5108 gibi bazı alt alellerinin Behçet Sendromlu hastalarla bağlantısı olduğu gözlemlenmiştir. Genom genelinde yapılan bağlantı çalışmalarında, IL-10, IL-23R, IL-12A, MICA, STAT4 gibi farklı genlerinde Behçet Senromu ile ilişkili olduğu bulunmuştur. Tüm bu bulgulara rağmen, HLA-B51 alelini taşıyan sağlıklı bireylerin varlığı, aynı şekilde HLA-B51 alelini taşımayan Behçet hastalarının varlığı, hastalığın oluşumunda başka mekanizmaların olabileceğini düşündürmüştür. DNA metilasyonu ve kromatin modifikasyonları gibi DNA dizisinde herhangi bir değişime sebep olmadan gen aktivitesini değiştiren epigenetik modifikasyonlar, tanımlanamayan kompleks hastalıkların nedenlerinin aydınlatılmasında önemli rol kazanmaktadır. Epigenetik modifikasyonlar içinde ise DNA metilasyonu en sık çalışılan regülasyon mekanizmalarından biridir. HLA-B geninde, 1346 nükleotit uzunluğundaki CpG adacığının varlığı ve bu bölgede CG dinükleotitlerinin %66.6 oranında yoğun olarak kümelendiği gözlemlenmiştir. CpG adacığında bulunan sitozin ve guanin bazlarının metillenmesi ile gen aktivitesinin dolayısıyla ekspresyonun değişmesi beklenmektedir. Yaptığımız öncül araştırmalarda, 4 monozigotik ve 4 dizigotik Behçet Sendrom’lu ikizlerin oluşturduğu çalışmamızda HLA-B geninin 1. ve 2. ekzonlarının epigenetik regülasyonunu düşündüren bulgulara rastladık. Bu çalışmada ise ailesel Behçet Sendromu vakaları ile birlikte ailelerinde bulunan diğer Behçet Sendrom’lu bireyler ve sağlıklı aile bireyleri de incelenmek istenmiştir. Bu sayede, HLA-B51 alelinin genetik ve epigenetik etkilerinin daha iyi anlaşılması planlanmıştır. 2013-2015 yılları arasında Cerrahpaşa Tıp Fakültesi Romatoloji Polikliniği’ne tedavi olmaya gelen hastalar içerisinden irtibat kurulan yaklaşık 100 Behçet Sendrom’lu bireyden, ailesinde en az bir BS tanısı konulmuş akrabası bulunan 50 Behçet Sendrom’lu bireye ulaşılmıştır. İletişime geçilen 50 Behçet Sendrom’lu aileden 15 aile çalışmamıza katılmayı kabul etmiştir. Araştırma grubumuz toplamda 15 Behçet Sendrom’lu birey, ailelerindeki Behçet Sendrom’lu 17 akraba ve yine ailelerindeki 26 sağlıklı akrabalardan oluşmaktadır. Hastalardan ve ailelerinden alınan periferal kan örneklerindeki lökositlerden genomik DNA izolasyonu yapılmıştır. Çalışma grubunda bulunan tüm bireyler, bölge spesifik Polimeraz Zincir Reaksiyonu yöntemiyle HLA-B51 aleli için genotiplenmiştir. Yapılan çalışmalar sonucunda, HLA-B51 pozitifliği, indeks hasta grubu için 12/15, hasta akrabalar için 13/17 ve sağlıklı akrabalar için 22/26 olarak hesaplanmıştır. 25 kişiden oluşan aile dışı sağlıklı kontrollerde ise HLA-B51 pozitifliği 8/25 oranında bulunmuştur. HLA-B51 genotiplendirmesi sonrasında, HLA-B geninin 1.ekzon, 1.intron ve 2.ekzon bölgelerinin metilasyon seviyeleri Real-time PCR temelli OneStep qMethyl kiti kullanılarak analiz edilmiştir. HLA-B genine ait ekzon-1, intron-1 ve ekzon-2 bölgelerini içeren metilasyon analizlerinde, indeks hasta grubu ve ailelerindeki diğer Behçet Sendrom’lu ve sağlıklı bireyler arasında yapılan karşılaştırmada, tüm Behçet Sendrom’lu bireylerdeki metilasyon oranlarının sağlıklı akrabalarına göre anlamlı olarak yüksek olduğu görülmüştür (p=0.0065). Fakat tüm gruplar ayrı ayrı incelendiğinde, HLA-B51 taşıyıcılığının metilasyon seviyeleri üzerinde anlamlı bi fark yaratmadığı ortaya çıkmıştır. Elde ettiğimiz sonuçlar, Behçet ikizleriyle yaptığımız önceki çalışmamızın sonuçlarıyla tutarlı olarak bulunmuştur. Bu veriler ışığında, HLA-B51 alelinden bağımsız olarak muhtemel epigenetik mekanizmaların, hastalığın oluşumunda etkili olabileceği düşünülmüştür. Bu çalışmanın devamı niteliğinde, epigenetik mekanizmaların değişken olabildiği göz önünde bulundurularak, Behçet Sendrom’lu ailelelerdeki sağlıklı akrabalar, ortaya çıkabilecek çeşitli Behçet Sendromu benzeri bulgular açısından takip altında tutulmalıdır. Aynı şekilde HLA-B bölgesinde saptanmış DNA metilasyon farklılıklarının gen ekspresyonuna etkisinin görülmesi amacıyla, aynı bölge için gen ekpresyonu analizleri yapılmalıdır. Bu çalışmalara ek olarak, münferit Behçet vakalarında da aynı şekilde, HLA-B51 genotiplemesi ve HLA-B bölgesi için DNA metilasyon analizleri tekrarlanmalıdır. Bu sayede ailesel ve münferit vakalarda HLA-B51 sıklığı ve HLA-B genindeki DNA metilasyon farklılıkları gözlemlenebilir. Gelecekte yapılacak çalışmalar için, HLA-B51 aleline spesifik metilasyonun araştırılması, gen içerisinde ya da genler arasında etkili olabilecek faktörlerin anlaşılmasında yararlı olacaktır. Buna ek olarak, HLA-B5101 ve HLA-B5108 gibi alt alel farklılıkları, Behçet Sendrom’lu bireyler arasında saptanarak, alt alel değişimlerinin hastalık üzerindeki etkisi gösterilebilir., Behçet’s Syndrome (BS) is a chronic multisystemic inflammatory disorder, primary symptoms of which are oral and genital ulceration and uveitis. The disease is also chracterized by inflammation in tissues and organs throughout the body such as vessels, lungs, kidneys, joints, gastrointestinal and central nervous system. BS usually occurs in second and third decades of the life with a severe disease course. It exists most commonly in Mediteranean and Middle East populations. In Turkey, frequency of the disease changes between 20 and 420 of 100.000. BS risk factors include genetic predisposition which is mainly based on familial aggregation and increased HLA-B51 carrier rate as well as infectious agents, environmental causes and yet undefined immunological mechanisms. Even though HLA-B51 allele has shown to be the most associated marker for BS, the presence of healthy individuals who carry HLA-B51 allele and similarly BS patients without HLA-B51 allele have led us question other mechanisms for BS causation. Epigenetic mechanisms have gained exceeding importance for their effects on DNA and chromatin structures without altering DNA sequence. DNA methylation is one of the mostly studied epigenetic mechanisms. HLA-B gene has shown to comprise a CpG island (CpGi) which span 1346 nucletides where CG ratio is 66.6 %, therefore methylation of cytosine residues may lead to a change in gene expression levels. We previously investigated global methylation and HLA-B locus specific methylation in a group of 4 MZ BS twins and 4 DZ BS twins; which suggested an involvement of an epigenetic regulation in HLA-B exon 1-2 region. BS twins had a higher methylation levels for HLA-B gene (p=0.0024). In this thesis we wanted to further our preliminary findings in familial BS cases and more directly examine the influence of HLA-B51 carrier rate and its methylation upon the presence of the clinical phenotype. Therefore, involvement of genetic and epigenetic roles of HLA-B51 region in BS would be better analysed and the sample size would be increased by including familial BS cases with their affected and unaffected relatives. 100 BS patients were contacted from Cerrahpaşa Medical Faculty, Rheumatology Polyclinic between 2013 and 2015 and asked if they have an affected relative. Within those 1800 index patients, 150 patients had a family member with BS. Among those, 15 families accepted to enroll in the study. So the study consists of 15 index patients; 17 affected relatives and 26 unaffected relatives. Peripheral blood samples were collected and genomic DNA was isolated from leukocytes. Patients and relatives were genotyped for HLA-B51 alleles using sequence specific PCR method. HLA-B51 positivity ratio was found to be 12/15 for index patients, 13/17 for affected relatives , 22/26 for unaffected relatives. Among BS and healthy family members, HLA-B51 frequency did not show a statistically significant diffrence. For healthy controls, who are not related with families, HLA-B51 positivity was 8/25. However, HLA-B51 positivity for BS patients was statistically higher when compared to healthy controls (p=0.0005). After determining HLA-B51 positivity, methylation profiles on HLA-B gene were analyzed and compared between groups using Real-time PCR based OneStep qMethyl Kit. For exon-1 and exon-2 region of HLA-B gene, BS patients had statistically higher methylation levels compared with healthy individuals in the family (p=0.0065). Methylation levels were not significantly different among HLA-B51(+) and HLA-B51(-) individuals for index patients, relatives with BS and healthy relatives. Observed results were also correlated with the data from our previous studies. These findings suggested us a room for epigenetic modifications which might be independent from HLA-B51 positivity., Yüksek Lisans, M.Sc.

Germ line BRCA1 and/or BRCA2 mutations were screened in 50 Turkish breast and/or ovarian cancer patients composed of hereditary, familial, early onset and male cancer groups. Genomic DNA samples were tested by heteroduplex analysis and DNA sequencing. Two truncating BRCA2 mutations, one novel (6880 insG) and one previously reported (3034 delAAAC), were found in two out of six (33%) hereditary breast and/or ovarian cancer patients. A novel truncating (1200 insA) and a missense (2080A!G) BRCA1 mutation was found in two of 27 (7%) individuals in the early onset group. A total of four (8%) disease-causing mutations in 50 breast cancer patients were identified in BRCA1 and BRCA2 genes. In addition, five BRCA1 sequence variants have been identified in 23 patients. These results indicate that BRCA1 and BRCA2 genes are involved in some, but not all, forms of hereditary predisposition to breast cancer in the Turkish population. # 2000 Published by Elsevier Science Ltd.

The validity of diagnostic definitions in psychiatry is directly related to the extent to which their etiology can be specified. However, since detailed knowledge of causal or susceptibility factors is lacking for most psychiatric disorders with a known or suspected familial-genetic origin, the current widely accepted classification systems largely fail to achieve this ideal. To illustrate this problem, this paper looks at the difficulties posed by the criteria for schizophrenia as laid down in the International Classification of Diseases, 10th revision (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R), and highlights the discrepancies between the majority of diagnostic boundaries and the various phenotype aggregation patterns observed in family studies. Progress in our understanding of psychiatric disorders requires to be firmly based on the findings of epidemiological studies as well as on a clear appreciation of the limitations of classification tools.

Familial combined hyperlipidemia (FCHL) is a frequent cause of premature coronary artery disease. Affected family members are characterized by different combinations of elevated cholesterol and/or triglyceride levels. A reduction in lipoprotein lipase (LPL) activity has been observed in a subgroup of FCHL patients. Recently, we have demonstrated an increased frequency of mutations in the LPL gene in Dutch FCHL patients compared to normolipidemic controls. In the present study, we have applied a pedigree- based maximum likelihood method to study the effect of LPL mutations on the phenotypic expression of FCHL in families. In 40 FCHL probandi, three different previously reported mutations in the LPL gene were identified resulting in amino acid changes, D9N, N291S, and S447X. The D9N mutation in exon 2 appeared to be in strong linkage disequilibrium with a T → G substitution at position - 93 in the promoter region of the LPL gene. We present data that the - 93T → G/D9N haplotype is associated with significantly higher levels of LDL and VLDL cholesterol, and VLDL triglycerides. Interestingly, the effect was only observed in male carriers. In line with our previous observations, these results further sustain that the LPL gene is a susceptibility gent for dyslipidemia which explains part of the variability in the phenotype observed among FCHL family members.

Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies. © 2014 Papazachariou et al. 9 12 Cited By :13

Humans have developed the perception, production and processing of sounds into the art of music. A genetic contribution to these skills of musical aptitude has long been suggested. We performed a genome-wide scan in 76 pedigrees (767 individuals) characterized for the ability to discriminate pitch (SP), duration (ST) and sound patterns (KMT), which are primary capacities for music perception. Using the Bayesian linkage and association approach implemented in program package KELVIN, especially designed for complex pedigrees, several single nucleotide polymorphisms (SNPs) near genes affecting the functions of the auditory pathway and neurocognitive processes were identified. The strongest association was found at 3q21.3 (rs9854612) with combined SP, ST and KMT test scores (COMB). This region is located a few dozen kilobases upstream of the GATA binding protein 2 (GATA2) gene. GATA2 regulates the development of cochlear hair cells and the inferior colliculus (IC), which are important in tonotopic mapping. The highest probability of linkage was obtained for phenotype SP at 4p14, located next to the region harboring the protocadherin 7 gene, PCDH7. Two SNPs rs13146789 and rs13109270 of PCDH7 showed strong association. PCDH7 has been suggested to play a role in cochlear and amygdaloid complexes. Functional class analysis showed that inner ear and schizophrenia-related genes were enriched inside the linked regions. This study is the first to show the importance of auditory pathway genes in musical aptitude.

The relationship between genetic polymorphism and imipramine metabolism has never been studied in a family study. A sparteine/mephenytoin test was carried out in 31 parents and 20 siblings of 18 Danish poor metabolizers of sparteine (PMs). One week later, each subject took 25 mg imipramine followed by urine collection for 24 h. The urinary content of imipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by HPLC. There were 10 PMs (20%; 9.8-33%, 95% confidence interval) and 41 extensive metabolizers of sparteine (EMs) among parents and siblings. In 26 of the 28 PMs among probands and relatives, there were concordance between phenotype and genotype: D6-A/D6-D (n = 2), D6-A/D6-B (n = 5), D6-B/(n = 15) or D6-B/D6-D (n = 4). Two PMs were apparently heterozygous (EMs), D6-wt/D6-B. Accordingly, based on the present sample of 28 PMs the specificity of the genotype test was 100% and the sensitivity was 92.9%. Two EMs were homozygous dominant D6-wt/and 39 were heterozygous EMs; D6-wt/D6-D (n = 5), D6-wt/D6-B (n = 27), D6-wt/D6-A (n = 6), D6-wt/D6-wt* (unknown mutation) (n = 1). As previously reported in a population study the hydroxylation ratios (i.e. 2-hydroxymetabolite over parent compound) of imipramine were much lower in PMs than in EMs. This and the pedigrees confirmed the co-segregation of sparteine oxidation, imipramine 2-hydroxylation and the CYP2D6 genotype. None of the hydroxylation ratios could separate EMs and PMs completely, mainly because the 2-hydroxylation of imipramine also depends on P450s other than CYP2D6.

Aims: To describe the familial occurrence of paracentric inversion of chromosome 3. Presentation of Cases: Patient 1: Female, Caucasian, born in Southeast of Brazil, 7 years old. Born at term and asphyxia. Developmental delay; aggressive behavior and tendency toward isolation. Prominent forehead, discrete epicanthal folds, down-slanting palpebral fissures, long philtrum and hypermobility of the four limbs. Karyotype: 46,XX,inv(3)(p13p25). Patient 2: Female, Caucasian, born in Northeast of Brazil, 3 years old. Born prematurely by cesarean section, pelvic presentation and asphyxia. Severe developmental delay. Microcephaly, bilateral convergent strabismus, epicanthal folds, wide nasal bridge, micrognathia, high arched palate and nasolabial hemangioma, low set ears, hypoplastic nipples, nucal café-au-lait spots, deep plantar fold. Dysgenesis of the corpus callosum. Karyotype: 46,XX,inv(3)(p13p25). Patient 3: Male, Caucasian, born in Southeast of Brazil, 5 years. Born at term, by cesarean section, cephalic presentation. Developmental delay and flexor spasms. Dolichocephalic skull, prominent forehead, ocular hypertelorism, epicanthal folds, disproportioned and low set ears, single palmary crease in the right hand, large and elongated thumbs, hypotonia, and recurrent acute otitis. Karyotype: 46,XY,inv(3)(p13p25). Discussion: Patients presented developmental delay and dysmorphic features, but the relatives that presented the same inversion were asymptomatic. Carriers seem to have a normal reproductive fitness, without differences between males and females. Conclusion: The chromosomal rearrangements, especially balanced chromosomal alterations provide an opportunity to broaden the understanding of the structure and functional organization of chromosomes and to offer better genetic counseling for the families.

Evidence for a major role of genetic factors in the determination of body mass index (BMI) comes from studies of related individuals. Despite consistent evidence for a heritable component of BMI, estimates of BMI heritability vary widely between studies and the reasons for this remain unclear. While some variation is natural due to differences between populations and settings, study design factors may also explain some of the heterogeneity. We performed a systematic review that identified 88 independent estimates of BMI heritability from twin studies (total 140,525 twins) and 27 estimates from family studies (42,968 family members). BMI heritability estimates from twin studies ranged from 0.47 to 0.90 (5th/50th/95th centiles: 0.58/0.75/0.87) and were generally higher than those from family studies (range: 0.24–0.81; 5th/50th/95th centiles: 0.25/0.46/0.68). Meta-regression of the results from twin studies showed that BMI heritability estimates were 0.07 (P = 0.001) higher in children than in adults; estimates increased with mean age among childhood studies (+0.012/year, P = 0.002), but decreased with mean age in adult studies (−0.002/year, P = 0.002). Heritability estimates derived from AE twin models (which assume no contribution of shared environment) were 0.12 higher than those from ACE models (P

A substantial part of the contribution of genetic studies to the treatment of schizophrenia involves its emphasis on reliable and valid diagnoses. One consequence of this focus is the recognition that schizophrenic illness is broader than the diagnostic entity of schizophrenia itself, and instead consists of a “spectrum” of related disorders. Because some of the symptoms in these disorders differ from each other, they provide an opportunity to determine which ones reflect a common etiology. To the extent that such symptoms are identifiable, they may provide a foundation for treatment and even prevention strategies. In this paper, we focus on a clinical condition - “schizotaxia” - that may reflect the liability for schizophrenia. To characterize the nature and extent of this proposed syndrome, we will review results from family studies in our laboratory, and consider conceptual foundations and criteria for assessment. A more general consideration of treatment strategies for schizophrenia spectrum disorders follows, along with suggestions for future research. Our initial attempts to treat and validate schizotaxia are encouraging, and raise the possibility that early treatment might eventually prevent or attenuate the development of other, more severe disorders in the schizophrenia spectrum, including schizophrenia itself.

Social cognitive deficits are associated with psychotic symptoms, but the nature of this association remains unknown. This study uses a genetically sensitive cross-trait cross-sibling design to investigate the nature of the overlap between both phenotypes. A sample of 1032 patients, 1017 of their healthy siblings, and 579 control subjects were recruited within the Dutch Genetic Risk and Outcome in Psychosis (GROUP) study. Participants completed a battery of cognitive tests, including 2 social cognitive tests on theory of mind (ToM) and emotion recognition. Within siblings, symptoms were assessed with the Structured Interview for Schizotypy-Revised. The Positive and Negative Syndrome Scale was used to assess patients' symptoms. Within patients, social cognitive performance was consistently and significantly associated with disorganized and, to a lesser degree, with negative symptoms. Associations with positive symptoms were significant, but smaller. Suggestive of a shared etiology, both social cognitive factors showed significant familial clustering. The associations between patients' ToM and subclinical symptoms in siblings were nonsignificant, suggesting that their overlap within patients is due to individual rather than shared familial factors. Indicative of a shared etiology, familial covariation was present between patients' emotion recognition ability and disorganized and, albeit to a lesser degree, positive but not negative subclinical symptoms in siblings. © 2011 The Author.

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P

Mutations in the genes coding for the proα1 and proα2 chains of type I procollagen have been found in many patients with osteogenesis imperfecta (OI), a heritable disorder of connective tissue. The severity of the disease varies between families and even among members of the same family. This phenotypic variability covers a spectrum extending from very mild forms that cannot be easily detected to perinatally lethal forms. One explanation for this phenotypic variability is the nature of the mutation in the type I procollagen genes. Another explanation is mosaicism. Here we report on 2 families with propositi who have OI, whereas their mothers had a milder form of the disease. In one family, the molecular defect was previously shown to be a substitution of α1904 by cysteine [Constantinou et al., 1990]. The biochemical phenotype was characterized by significant post-translational over-modification of the mutated type 1 collagen molecules which also had a 3-4°C decrease in their thermal unfolding. Also, secretion of the procollagen into the culture media was delayed. In the second family, the proposita's muscle fibroblasts synthesized and secreted type I procollagen molecules that were highly over-modified along the entire length of their triple-helical domain. Cells from the mother also synthesized normal and over-modified protein, although the amount of over-modified protein was less than that synthesized by her daughter's cells. The exact molecular defect has not yet been defined. The simplest explanation for the phenotypic variability seen within these 2 families is that the mothers of the propositi are mosaic for their respective mutations so that not all of their somatic cells produce abnormal type I procollagen. Hence, one additional explanation for the phenotypic variability in OI is the abundance of the mutated allele or the degree of mosaicism in the patient's population of cells so that the first affected individual in a family may be mildly affected by a mutation which in a heterozygous form is potentially lethal in his or her offspring. 45 246 251 Cited By :14

The genetic causes of the components of cardiovascular disease (CVD) risk factors and their intercorrelation are indeed complex and only partly understood. Keeping this view in mind, the present work was undertaken to estimate the heritability of conventional CVD risk factors using family study method. A total of twenty-four nuclear families inhabiting in Calcutta and adjacent areas was chosen randomly. Up to first degree relatives including father, mother and other sibs of the proband were considered as participants in the study. Anthropometric measures namely height, weight, waist circumference as well as skinfold thickness at biceps, triceps, subscapular and suprailiac were obtained using standard techniques. Body mass index (BMI), percentage of body fat (PBF), fat mass (FM), waist-hip ratio (WHR), sum of four skinfolds (SF(4) ), arm muscle circumference (AMC), arm muscle area (AMA), arm fat area (AFA), systolic (SBP) and diastolic blood pressure (DBP) were also considered. To estimate'heritability' in the study, the mid parent-offspring model was used where'heritability' (h(2) ) was equivalent to regression co-efficient (b). The regression sum of square (RSS) and total sum of square (TSS) ratio was also calculated both for mid parent-offspring and single parent-offspring. This ratio was considered as a measure of'heritability' in the study with consideration that RSS is the variation due to genetic factor and the TSS is due to genetic and other additive factor. It was observed that the estimated heritability for BMI ranges from 0.69 to 0.31 using mid-parent off spring model while the range using single parent-offspring model was from 0.40 to 0.16. The range of heritability for SBP in mid parent-offspring model was 0.16 to 0.44 and 0.05 to 0.54 for single parent-offspring model. To conclude, it seems reasonable to argue that in the study a moderate to high h(2) was evident for body fat level, body composition and blood pressure measures which indicate a moderate to high aggregation of gene(s) in the family.