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This paper aims to clarify the mechanism linking media coverage and advertising to electoral volatility. It is argued that the link is indirect rather than direct: Parties' communication affects electoral volatility because it alters citizens' perceptions of party competence. In addition, it examines differences between communication channels – media coverage and advertising – and between individuals. Three data sources on Switzerland are used to test these relationships: an individual rolling cross-section panel data, a media content analysis, and an advertisement content analysis. Mediation models show that the visibility of parties on issues influences perceptions of competence and thereby helps parties to attract new voters and reinforce their core voters. Furthermore, ads seem to have a stronger effect than media coverage in reinforcing people's opinions. Finally, and in line with motivated reasoning, citizens without partisan ties are more sensitive to campaign information than party identifiers. [ABSTRACT FROM AUTHOR]

Whether human sexuality is the result of nature or nurture (or their complex interplay) represents a hot, often ideologically driven, and highly polarized debate with political and social ramifications, and with varying, conflicting findings reported in the literature. A number of heritability and behavioral genetics studies, including pedigree-based investigations, have hypothesized inheritance patterns of human sexual behaviors. On the other hand, in most twin, adoption, and nuclear family studies, it was not possible to disentangle between underlying genetic and shared environmental sources. Furthermore, these studies were not able to estimate the precise extent of genetic loading and to shed light both on the number and nature of the putative inherited factors, which remained largely unknown. Molecular genetic studies offer an unprecedented opportunity to overcome these drawbacks, by dissecting the molecular basis of human sexuality and allowing a better understanding of its biological roots if any. However, there exists no systematic review of the molecular genetics of human sexuality. Therefore, we undertook this critical systematic review and appraisal of the literature, with the ambitious aims of filling in these gaps of knowledge, especially from the methodological standpoint, and providing guidance to future studies. Sixteen studies were finally retained and overviewed in the present systematic review study. Seven studies were linkage studies, four studies utilized the candidate gene approach, and five studies were GWAS investigations. Limitations of these studies and implications for further research are discussed. [ABSTRACT FROM AUTHOR]

Objectives: The association between obsessive–compulsive disorder (OCD) and sexually transmitted infections (STIs) and the effects of OCD medication on STI risk remain unknown. In the present study, we intended to study the risks of subsequent STIs after an OCD diagnosis and the effects of related OCD medications on STI risk. Methods: With the Taiwan National Health Insurance Research Database, we enrolled 15,908 adolescent and young adult patients with OCD and 159,080 age- and sex-matched individuals without OCD between 2001 and 2009, and followed them up until the end of 2011 for subsequent STI diagnoses. Results: The total patients with OCD were significantly more to acquire an STI, with a hazard ratio (95% confidence interval) being 3.25 (2.61–4.03), than their counterparts without OCD (p < 0.05). The associations between OCD medications, including antidepressants, mood stabilizers, and second-generation (atypical) antipsychotic drugs, and subsequent STI risk did not reach any significant differences. Conclusion: In this study, we found that OCD is an independent risk factor of acquiring any STI in the adolescent and young adult population. We recommend that clinicians should be more alert in identifying risky sexual behaviors and STI risks in such patients with OCD.

Background: Increasing studies have supported the relationship between pain disorders and treatment-resistant depression (TRD) or chronic pain disorders may possibly impact the clinical characteristics of major depressive disorder (MDD). Thus, this linkage has been seen as a potential clinical marker to predict diagnostic conversion to bipolar disorder (BD) among patients with MDD. Methods: With the Taiwan National Health Insurance Research Database, we enrolled 4,760 adolescent and young adult patients with TRD, 19,040 counterparts with antidepressant-responsive depression, and 19,040 age-/sex-/residence-/family income-matched controls. Then, we followed up on their conversion from MDD to BD from enrollment to the end of 2011. Results: The incidence of diagnostic progression from MDD to BD was significantly higher in the TRD group than the non-TRD group (30.5% versus 10.6%, p < 0.001). Logistic regression analysis with adjustment of demographic characteristics showed that the TRD group had the highest risks of previous migraine, tension headache, fibromyalgia, peripheral neuropathy, dysmenorrhea, and irritable bowel syndrome, followed by the non-TRD group, and then the control group (p < 0.05). In further analysis of those data stratified by diagnostic progression to BD, we found no consistent results among different subgroups. Conclusion: Clinicians should be aware of the higher risk of developing TRD in depressive patients with comorbid pain disorders such as migraine, tension headache, fibromyalgia, peripheral neuropathy, dysmenorrhea, and irritable bowel syndrome. Besides, we found no consistent results in predicting diagnostic conversion from MDD to BD when the rôle of these pain disorders was evaluated.

AbstractAim The aim of this study was to compare the prevalence of daytime contacts and consultations, and pain as a reason for encounter (RFE) with a general practitioner (GP), in children with cerebral palsy (CP) (cases) to that of the general paediatric population (controls).Methods The study linked the Norwegian Directorate of Health’s database for the control and reimbursement of health expenses, and the Norwegian Quality and Surveillance Registry for Cerebral Palsy, including children born from 1996 to 2012 in the period 2006 to 2018. All daytime contacts were included. International Classification for Primary Care was applied for RFE.Results Cases accounted for 0.46% of all daytime contacts and 0.27% of all daytime consultations, the latter corresponding with the estimated national prevalence of CP. GPs registered more administrative contact and coded pain as an RFE less frequently in consultations with cases (6%) than with controls (12%).Interpretation Children with CP did not consult GPs more than the general paediatric population did. In consultations, GPs should ask for pain even if the child with CP or parent does not address pain. The local multidisciplinary team should encourage the family to consider consulting a GP if the child is in pain.KEY MESSAGESPrevalence of GP consultations in children with CP is similar to that of children in the general population.GPs perform more administrative work for children with CP than for their other paediatric patients.GPs code pain as an RFE less frequently in consultations with children with CP than in consultations with children in the general population.

Whether human sexuality is the result of nature or nurture (or their complex interplay) represents a hot, often ideologically driven, and highly polarized debate with political and social ramifications, and with varying, conflicting findings reported in the literature. A number of heritability and behavioral genetics studies, including pedigree-based investigations, have hypothesized inheritance patterns of human sexual behaviors. On the other hand, in most twin, adoption, and nuclear family studies, it was not possible to disentangle between underlying genetic and shared environmental sources. Furthermore, these studies were not able to estimate the precise extent of genetic loading and to shed light both on the number and nature of the putative inherited factors, which remained largely unknown. Molecular genetic studies offer an unprecedented opportunity to overcome these drawbacks, by dissecting the molecular basis of human sexuality and allowing a better understanding of its biological roots if any. However, there exists no systematic review of the molecular genetics of human sexuality. Therefore, we undertook this critical systematic review and appraisal of the literature, with the ambitious aims of filling in these gaps of knowledge, especially from the methodological standpoint, and providing guidance to future studies. Sixteen studies were finally retained and overviewed in the present systematic review study. Seven studies were linkage studies, four studies utilized the candidate gene approach, and five studies were GWAS investigations. Limitations of these studies and implications for further research are discussed.

The aim of this study was to compare the prevalence of daytime contacts and consultations, and pain as a reason for encounter (RFE) with a general practitioner (GP), in children with cerebral palsy (CP) (cases) to that of the general paediatric population (controls). The study linked the Norwegian Directorate of Health's database for the control and reimbursement of health expenses, and the Norwegian Quality and Surveillance Registry for Cerebral Palsy, including children born from 1996 to 2012 in the period 2006 to 2018. All daytime contacts were included. International Classification for Primary Care was applied for RFE. Cases accounted for 0.46% of all daytime contacts and 0.27% of all daytime consultations, the latter corresponding with the estimated national prevalence of CP. GPs registered more administrative contact and coded pain as an RFE less frequently in consultations with cases (6%) than with controls (12%). Children with CP did not consult GPs more than the general paediatric population did. In consultations, GPs should ask for pain even if the child with CP or parent does not address pain. The local multidisciplinary team should encourage the family to consider consulting a GP if the child is in pain. Prevalence of GP consultations in children with CP is similar to that of children in the general population. GPs perform more administrative work for children with CP than for their other paediatric patients. GPs code pain as an RFE less frequently in consultations with children with CP than in consultations with children in the general population. [ABSTRACT FROM AUTHOR]

Purpose: We determined the prevalence of untreated depression in patients with hypertension (HT) and/or diabetes (DM) and estimated the extra health care use and expenditures associated with this comorbidity in a rural Hungarian adult population. We also assessed the potential workload of systematic screening for depression in this patient group.Methods: General health check database from a primary care programme containing survey data of 2027 patients with HT and/or DM was linked to the outpatient secondary care use database of National Institute of Health Insurance Fund Management. Depression was ascertained by Beck Depression Inventory score and antidepressant drug use. The association between untreated depression and secondary healthcare utilization indicated by number of visits and expenses was evaluated by multiple logistic regression analysis controlled for socioeconomic/lifestyle factors and comorbidity. The age-, sex- and education-specific observations were used to estimate the screening workload for an average general medical practice.Results: The frequency of untreated depression was 27.08%. The untreated severe depression (7.45%) was associated with increased number of visits (OR 1.60, 95% CI 1.11-2.31) and related expenses (OR 2.20, 95% CI 1.50-3.22) in a socioeconomic status-independent manner. To identify untreated depression cases among patients with HT and/or DM, an average GP has to screen 42 subjects a month.Conclusion: It seems to be reasonable and feasible to screen for depression in patients with HT and/or DM in the primary care, in order to detect cases without treatment (which may be associated with increase of secondary care visits and expenditures) and to initiate the adequate treatment of them. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background & objectives: Hearing impairment is a common and heterogeneous sensory disorder in humans. Among about 90 genes, which are known to be associated with hearing impairment, mutations in the GJB2 (gap junction protein beta 2) gene are the most prevalent in individuals with hereditary hearing loss. Contribution of the other deafness-causing genes is relatively poorly understood. Here, we present our findings on two families with transmembrane channel like 1 (TMC1) gene variants of the 47 families with nonsyndromic hearing loss (NSHL) studied. Methods: Forty seven families including 26 consanguineous families with at least two hearing impaired children and one normal hearing child and 21 non-consanguineous families having at least three hearing impaired children and one normal hearing child were enrolled for this study. Genetic linkage studies were carried out in 41 families that were GJB2 (Connexin 26) negative. Seven polymorphic short tandem repeat markers at the DFNB7/11 locus were studied employing fluorescently labelled markers. Results: A novel homozygous missense mutation c.1283C>A (p.Ala428Asp) was identified co-segregating with hearing loss. This change results in substitution of a highly conserved polar alanine to a charged aspartic acid and is predicted to be deleterious. In addition, a previously reported nonsense mutation, p.R34X in TMC1, was found. Interpretation & conclusions: While mutations in TMC1 are not as common a cause of NSHL as those in GJB2, TMC1 should be considered for diagnostic investigations in cases of NSHL in GJB2-negative families. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: Hemophilia A is an X-linked recessive inherited disease that its frequency is reported as 1 in 5000 to 10000 males. Linkage analysis is widely used in related female of hemophilic family around the world. In this study, 3 intragenic polymorphism markers including G/A in intron 7, T/A polymorphism in intron 18 and C/T polymorphism in intron 19 were introduced as the most informative markers for the linkage analysis of factor eight gene. This research was designed to determine the carrier people and give knowledge to the families in risk for the birth of another affected child on those families.METHODS: In this cross-sectional study, 20 hemophiliacs A families including 30 patients and 64 family members (father, mother, sisters, aunt, and their children and other relative, who had chance to be carrier) from 5 cities of Mazandaran province were investigated. At first, family history was collected and pedigree was drawn. Five to 10 milliliter peripheral bloods were collected from each person and then DNA was extracted. Molecular study was performed using ARMS-PCR method and using three mentioned markers. At last, carrier persons were identified regarding to the inheritance of the same affected chromosome in patients and other related females in the family and comparison of linkage phase in affected person and results achieved from related females.FINDINGS: From 95 individuals who were studied in 20 families, 28 related women to the hemophilia patients were diagnosed as obligate or possible carriers. Also the usefulness of each markers applied in this study were evaluated by calculation of the coefficient of heterozygocity for each polymorphic makers and following results were achieved: G/A in intron 7 (49.4%), T/A in intron 18 (41.17%) and C/T in intron 19 (42.35%).CONCLUSION: The results showed that polymorphic markers used in this study were highly informative and suitable for carrier detection of hemophilia A.

Several functional and morphological brain measures are partly under genetic control. The identification of direct links between neuroimaging signals and corresponding genetic factors can reveal cellular-level mechanisms behind the measured macroscopic signals and contribute to the use of imaging signals as probes of genetic function. To uncover possible genetic determinants of the most prominent brain signal oscillation, the parieto-occipital 10-Hz alpha rhythm, we measured spontaneous brain activity with magnetoencephalography in 210 healthy siblings while the subjects were resting, with eyes closed and open. The reactivity of the alpha rhythm was quantified from the difference spectra between the two conditions. We focused on three measures: peak frequency, peak amplitude and the width of the main spectral peak. In accordance with earlier electroencephalography studies, spectral peak amplitude was highly heritable ( h2 > 0.75). Variance component-based analysis of 28 000 single-nucleotide polymorphism markers revealed linkage for both the width and the amplitude of the spectral peak. The strongest linkage was detected for the width of the spectral peak over the left parieto-occipital cortex on chromosome 10 ( LOD = 2.814, nominal P < 0.03). This genomic region contains several functionally plausible genes, including GRID1 and ATAD1 that regulate glutamate receptor channels mediating synaptic transmission, NRG3 with functions in brain development and HRT7 involved in the serotonergic system and circadian rhythm. Our data suggest that the alpha oscillation is in part genetically regulated, and that it may be possible to identify its regulators by genetic analyses on a realistically modest number of samples. [ABSTRACT FROM AUTHOR]

Substantial evidence exists suggesting that small, dense LDL particles are associated with an increased risk of coronary heart disease. This disease-related risk factor is recognized to be under both genetic and environmental influences. Several studies have been conducted to elucidate the genetic architecture underlying this trait, and a review of this literature seems timely. The methods and strategies used to determine its genetic component and to identify the genes have greatly changed throughout the years owing to the progress made in genetic epidemiology and the influence of the Human Genome Project. Heritability studies, complex segregation analyses, candidate gene linkage and association studies, genome-wide linkage scans, and animal models are all part of the arsenal to determine the susceptibility genes. The compilation of these studies clearly revealed the complex genetic nature of LDL particles.This work is an attempt to summarize the growing evidence of genetic control on LDL particle heterogeneity with the aim of providing a concise overview in one read.

Background Self-harm is a key risk factor for suicide and it is important to have contemporary information on the extent of risk. Methods Mortality follow-up to 2012 of 40,346 self-harm patients identified in the three centres of the Multicentre Study of Self-harm in England between 2000 and 2010. Results Nineteen per cent of deaths during the study period ( N =2704) were by suicide, which occurred in 1.6% of patients (2.6% of males and 0.9% of females), during which time the risk was 49 times greater than the general population risk. Overall, 0.5% of individuals died by suicide in the first year, including 0.82% of males and 0.27% of females. While the absolute risk of suicide was greater in males, the risk relative to that in the general population was higher in females. Risk of suicide increased with age. While self-poisoning had been the most frequent method of self-harm, hanging was the most common method of subsequent suicide, particularly in males. The number of suicides was probably a considerable underestimate as there were also a large number of deaths recorded as accidents, the majority of which were poisonings, these often involving psychotropic drugs. Limitations The study was focussed entirely on hospital-presenting self-harm. Conclusions The findings underline the importance of prevention initiatives focused on the self-harm population, especially during the initial months following an episode of self-harm. Estimates using suicide and open verdicts may underestimate the true risk of suicide following self-harm; inclusion of accidental poisonings may be warranted in future risk estimates. [ABSTRACT FROM AUTHOR]

Six hundred million people are at risk of infection by Schistosoma mansoni. MHC haplotypes have been reported to segregate with susceptibility to schistosomiasis in murine models. In humans, a major gene related to susceptibility/resistance to infection by S. mansoni (SM1) and displaying the mean fecal egg count as phenotype was detected by segregation analysis. This gene displayed a codominant mode of inheritance with an estimated frequency of 0.20-0.25 for the deleterious allele and accounted for more than 50% of the variance of infection levels. To determine if the SM1 gene segregates with the human MHC chromosomal region, we performed a linkage study by the lod score method. We typed for HLA-A, B, C, DR and DQ antigens in 11 informative families from an endemic area for schistosomiasis in Bahia, Brazil, by the microlymphocytotoxicity technique. HLA-DR typing by the polymerase chain reaction with sequence-specific primers (PCR-SSP) and HLA-DQ were confirmed by PCR-sequence-specific oligonucleotide probes (PCR-SSOP). The lod scores for the different q values obtained clearly indicate that there is no physical linkage between HLA and SM1 genes. Thus, susceptibility or resistance to schistosomiasis, as defined by mean fecal egg count, is not primarily dependent on the host's HLA profile. However, if the HLA molecule plays an important role in specific immune responses to S. mansoni, this may involve the development of the different clinical aspects of the disease such as granuloma formation and development of hepatosplenomegaly.

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder with high heritability. In recent years, numerous molecular genetic studies have been published to investigate susceptibility loci for ADHD. These results brought valuable candidates for further research, but they also presented great challenge for profound understanding of genetic data and general patterns of current molecular genetic studies of ADHD since they are scattered and heterogeneous. In this review, we presented a retrospective review of more than 300 molecular genetic studies for ADHD from two aspects: (1) the main achievements of various studies were summarized, including linkage studies, candidate-gene association studies, genome-wide association studies and genome-wide copy number variation studies, with a special focus on general patterns of study design and common sample features; (2) candidate genes for ADHD have been systematically evaluated in three ways for better utilization. The thorough summary of the achievements from various studies will provide an overview of the research status of molecular genetics studies for ADHD. Meanwhile, the analysis of general patterns and sample characteristics on the basis of these studies, as well as the integrative review of candidate ADHD genes, will propose new clues and directions for future experiment design. [Copyright &y& Elsevier]

We aimed to identify the region harboring a putative candidate gene associated with hippocampal abnormalities (HAb) in a family with mesial temporal lobe epilepsy (MTLE). Genome-wide scan was performed in one large kindred with MTLE using a total of 332 microsatellite markers at ~12cM intervals. An additional 13 markers were genotyped in the candidate region. Phenotypic classes were defined according to the presence of hippocampal atrophy and/or hyperintense hippocampal T2 signal detected on magnetic resonance imaging. We identified a significant positive LOD score on chromosome 18p11.31 with a Zmax of 3.12 at D18S452. Multipoint LOD scores and haplotype analyses localized the candidate locus within a 6cM interval flanked by D18S976 and D18S967. We present here evidence that HAb, which were previously related mainly to environmental risk factors, may be influenced by genetic predisposition. This finding may have major impact in the study of the mechanisms underlying abnormalities in mesial temporal lobe structures and their relationship with MTLE.

Aim: The aim of our study was to investigate whether the tandem repeat polymorphism in D18S452 microsatellite marker at locus 18p11.2 is a risk factor of bipolar affective disorder (BPAD) in Kashmiri population. Materials and Methods: The repeat polymorphism in D18S452 was evaluated by polymerase chain reaction (PCR) analysis of in 74 diagnosed BPAD patients and 74 controls subjects. Results: Tandem repeat (300 bp") allele frequency was found to be 1.35% in controls and 8.108% in cases. The tandem repeat (250 bp") allele frequency was found to be in 91.89% in cases and 98.65% in controls. The 252 bp/252 bp genotype was found to be present in 89.18% of cases and 98.64% of controls, the 300 bp/300 bp genotype in 5.40% of cases and 1.35% of controls and the 252 bp/300 bp variant in 5.40% of cases and none among the controls. Although the proportion of patients homozygous for tandem repeat (300 bp/300 bp) was higher in cases than in controls, the difference was not statistically significant when 252 bp/252 bp genotype was taken as reference (odds ratio [OR]=4.4242; 95% confidence interval [CI] 0.4822-40.5924); P=0.1529). However, when the frequency of heterozygous genotype (252 bp/300 bp) was compared with 252 bp/252 bp statistical significance was observed (OR=8.0603; 95% CI 1.1112-58.4646; P=0.0383). Conclusion: This is the first study reporting a significant association between D18S452 maker with tandem repeat polymorphism in heterozygous condition (252 bp/300 bp) and the development of BPAD in Kashmiri population. [ABSTRACT FROM AUTHOR]

Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences ( CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 5′UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227-DXS8091) to 4 Mb also disclosing a higher LOD score. [ABSTRACT FROM AUTHOR]

The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits. [ABSTRACT FROM AUTHOR]

Background: Frequently attending patients to primary care (FA) are likely to cost more in primary care than their non-frequently attending counterparts. But how much is spent on specialist care of FAs? We describe the healthcare expenditures of frequently attending patients during 1, 2 or 3 years and test the hypothesis that additional costs can be explained by FAs’ combined morbidity and primary care physicians’ characteristics. Methods: Record linkage study. Pseudonymised clinical data from the medical records of 16 531 patients from 39 general practices were linked to healthcare insurer’s reimbursements data. Main outcome measures were all reimbursed primary and specialist healthcare costs between 2007 and 2009. Multilevel linear regression analysis was used to quantify the effects of the different durations of frequent attendance on three-year total healthcare expenditures in primary and specialist care, while adjusting for age, sex, morbidities and for primary care physicians characteristics. Primary care physicians’ characteristics were collected through administrative data and a questionnaire. Results: Unadjusted mean 3-year expenditures were 5044 and 15 824 Euros for non-FAs and three-year-FAs, respectively. After adjustment for all other included confounders, costs both in primary and specialist care remained substantially higher and increased with longer duration of frequent attendance. As compared to non-FAs, adjusted mean expenditures were 1723 and 5293 Euros higher for one-year and three-year FAs, respectively. Conclusions: FAs of primary care give rise to substantial costs not only in primary, but also in specialist care that cannot be explained by their multimorbidity. Primary care physicians’ working styles appear not to explain these excess costs. The mechanisms behind this excess expenditure remain to be elucidated. [ABSTRACT FROM AUTHOR]

We aimed to identify the region harboring a putative candidate gene associated with hippocampal abnormalities (HAb) in a family with mesial temporal lobe epilepsy (MTLE). Genome-wide scan was performed in one large kindred with MTLE using a total of 332 microsatellite markers at s12cM intervals. An additional 13 markerswere genotyped in the candidate region. Phenotypic classes were defined according to the presence of hippocampal atrophy and/or hyperintense hippocampal T2 signal detected on magnetic resonance imaging. We identified a significant positive LOD score on chromosome 18p11.31 with a Z max of 3.12 at D18S452. Multipoint LOD scores and haplotype analyses localized the candidate locus within a 6-cM interval flanked by D18S976 and D18S967. We present here evidence that HAb, which were previously related mainly to environmental risk factors, may be influenced by genetic predisposition. This finding may have major impact in the study of the mechanisms underlying abnormalities in mesial temporal lobe structures and their relationship with MTLE. [ABSTRACT FROM AUTHOR]

We aimed to identify the region harboring a putative candidate gene associated with hippocampal abnormalities (HAb) in a family with mesial temporal lobe epilepsy (MTLE). Genome-wide scan was performed in one large kindred with MTLE using a total of 332 microsatellite markers at ∼12cM intervals. An additional 13 markers were genotyped in the candidate region. Phenotypic classes were defined according to the presence of hippocampal atrophy and/or hyperintense hippocampal T2 signal detected on magnetic resonance imaging. We identified a significant positive LOD score on chromosome 18p11.31 with a Zmax of 3.12 at D18S452. Multipoint LOD scores and haplotype analyses localized the candidate locus within a 6cM interval flanked by D18S976 and D18S967. We present here evidence that HAb, which were previously related mainly to environmental risk factors, may be influenced by genetic predisposition. This finding may have major impact in the study of the mechanisms underlying abnormalities in mesial temporal lobe structures and their relationship with MTLE. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM) is an autoimmune disease affecting approximately one in 300 individuals in the United States. The majority of genetic research to date has focused on the heritability that predisposes to islet autoimmunity and T1DM. The evidence so far points to T1DM being a polygenic, common, complex disease with major susceptibility lying in the major histocompatibility complex (MHC) on chromosome 6 with other smaller effects seen in loci outside of the MHC. With recent advances in technology, novel means of exploring the human genome have given way to new information in the development of T1DM. The newest technologies, namely high-throughput polymorphism typing and sequencing, have led to a paradigm shift in studying common diseases such as T1DM. In this review we highlight the advances in genetic associations in T1DM in the last several decades and how they have led to a better understanding of T1DM pathogenesis. [ABSTRACT FROM AUTHOR]

Celiac disease is a multifactorial disorder caused by an unknown number of genetic factors interacting with an environmental factor. Hence, most patients are singletons and large families segregating with celiac disease are rare. We report on a three-generation family with six patients in which the inheritance pattern is consistent with an autosomal dominant model. To date, 27 loci explain up to 40% of the heritable disease risk. We hypothesized that part of the missing heritability is because of low frequency or rare variants. Such causal variants could be more prominent in multigeneration families where private mutations might co-segregate with the disease. They can be identified by linkage analysis combined with whole exome sequencing. We found three linkage regions on 4q32.3-4q33, 8q24.13-8q24.21 and 10q23.1-10q23.32 that segregate with celiac disease in this family. We performed exome sequencing on two affected individuals to investigate the positional candidate regions and the remaining exome for causal nonsense variants. We identified 12 nonsense mutations with a low frequency (minor allele frequency <10%) present in both individuals, but none mapped to the linkage regions. Two variants in the CSAG1 and KRT37 genes were present in all six affected individuals. Two nonsense variants in the MADD and GBGT1 genes were also present in 5 of 6 and 4 of 6 individuals, respectively; future studies should determine if any of these nonsense variants is causally related to celiac disease. [ABSTRACT FROM AUTHOR]

Simulation of genotypes in pedigrees is an important tool to evaluate the power of a linkage or an association study and to assess the empirical significance of results. SLINK is a widely-used package for pedigree simulations, but its implementation has not previously been described in a published paper. SLINK was initially derived from the LINKAGE programs. Over the 20 years since its release, SLINK has been modified to incorporate faster algorithms, notably from the linkage analysis package FASTLINK, also derived from LINKAGE. While SLINK can simulate genotypes on pedigrees of high complexity, one limitation of SLINK, as with most methods based on peeling algorithms to evaluate pedigree likelihoods, is the small number of linked markers that can be generated. The software package SUP includes an elegant wrapper for SLINK that circumvents the limitation on number of markers by using descent markers generated by SLINK to simulate a much larger number of markers on the same chromosome, linked and possibly associated with a trait locus. We have released new coordinated versions of SLINK (3.0; available from http://watson.hgen.pitt.edu) and SUP (v090804; available from http://mlemire.freeshell.org/software or http://watson.hgen.pitt.edu) that integrate the two software packages. Thereby, we have removed some of the previous limitations on the joint functionality of the programs, such as the number of founders in a pedigree. We review the history of SLINK and describe how SLINK and SUP are now coordinated to permit the simulation of large numbers of markers linked and possibly associated with a trait in large pedigrees. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. Although the data from twin and family studies suggest an involvement of genetic factors in the familial transmission of PD with the heritability estimate near 40%, the genetic substrate underlying panicogenesis is not yet understood. The linkage studies so far have suggested that chromosomal regions 13q, 14q, 22q, 4q31–q34, and probably 9q31 are associated with the transmission of PD phenotypes. To date, more than 350 candidate genes have been examined in association studies of PD, but most of these results remain inconsistent, negative, or not clearly replicated. Only Val158Met polymorphism of the catechol-O-methyltransferase gene has been implicated in susceptibility to PD by several studies in independent samples and confirmed in a recent meta-analysis. However, the specific role of this genetic variation in PD requires additional analysis considering its gender- and ethnicity-dependent effect and putative impact on cognitive functions. The recent advantages in bioinformatics and genotyping technologies, including genome-wide association and gene expression methods, provide the means for far more comprehensive discovery in PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current controversies to more definitive findings. [ABSTRACT FROM AUTHOR]

Abstract: Otosclerosis is a common form of conductive hearing loss with a prevalence of 0.3–0.4% in white adults. It is characterized by labyrinthine endochondral sclerosis which may invade the stapedio-vestibular joint and interfere with free motion of the stapes. Both environmental factors and genetic causes have been implicated in the disease process; however, the pathogenesis of otosclerosis still remains poorly understood. To date, several loci have been mapped in families segregating autosomal dominant otosclerosis although no disease-causing mutations have been identified. In contrast, several association studies have implicated specific genes but their effects on risk-of-disease are small. The goal of this paper is to review the genetics of otosclerosis and to provide insight into studies that could be performed to elucidate disease pathogenesis. [Copyright &y& Elsevier]

Glaucoma is the leading cause of visual impairment and blindness throughout the world. Primary open angle glaucoma (POAG; MIM 137760) is the main type of glaucoma in most populations, and more than 20 genetic loci for POAG have been reported. Only three causative genes have been identified in these loci, viz. myocilin (MYOC), optineurin (OPTN), and WD repeat domain 36 (WDR36). However, mutations in these genes account for only a small percentage of the patients with POAG. Some of these glaucoma cases have a Mendelian inheritance pattern, and a considerable fraction of the cases result from a large number of variants in several genes each contributing small effects. Glaucoma is considered to be a common disease such as diabetes mellitus, coronary disease, Crohn disease, and several( )common cancers. The main technological approaches used to identify the genes associated with glaucoma are the candidate gene approach, linkage analysis, case-control association study, and genome-wide association study. Association studies have found about 27 genes related to POAG, but the glaucoma-causing effects of these genes need to be investigated in more detail. The current trend is to use case-control association studies or genome-wide association studies to map the genes associated with glaucoma. Such studies are expected to greatly advance our understanding of the genetic basis of glaucoma, and to provide information on the effectiveness of glaucoma therapy. This review gives an overview on the genetic aspects of glaucoma. [ABSTRACT FROM AUTHOR]