Genetic Linkage Studies Research Articles

Trichotillomania comorbidity in a sample enriched for familial obsessive-compulsive disorder

BackgroundThis study addresses the strength of associations between trichotillomania (TTM) and other DSM-IV Axis I conditions in a large sample (n = 2606) enriched for familial obsessive-compulsive disorder (OCD), to inform TTM classification. MethodsWe identified participants with TTM in the Johns Hopkins OCD Family Study (153 families) and the OCD Collaborative Genetics Study, a six-site genetic linkage study of OCD (487 families). We used logistic regression (with generalized estimating equations) to assess the strength of associations between TTM and other DSM-IV disorders. ResultsTTM had excess comorbidity with a number of conditions from different DSM-IV chapters, including tic disorders, alcohol dependence, mood disorders, anxiety disorders, impulse-control disorders, and bulimia nervosa. However, association strengths (odds ratios) were highest for kleptomania (6.6), pyromania (5.8), OCD (5.6), skin picking disorder (4.4), bulimia nervosa (3.5), and pathological nail biting (3.4). ConclusionsTTM is comorbid with a number of psychiatric conditions besides OCD, and it is strongly associated with other conditions involving impaired impulse control. Though DSM-5 includes TTM as an OCD-related disorder, its comorbidity pattern also emphasizes the impulsive, appetitive aspects of this condition that may be relevant to classification.

Genetic disposition to primary hyperhidrosis: a review of literature.

Primary hyperhidrosis is a condition characterized by excessive sweating. The estimated prevalence is between 0.6 and 4.4%, and it can have economic, psychological, and social consequences for affected individuals. Family and genetic studies have suggested a genetic component in the inheritance of the disease. In this review, we summarize the current literature on genetic disposition to primary hyperhidrosis. We Identified 20 studies on Pubmed and Embase in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Probands reported a positive family history in 5.7-65% of cases, and the inheritance appeared to be either autosomal dominant or recessive. Individuals with palmoplantar phenotypes and a positive family history had a younger age of onset. Genetic linkage and genome-wide association studies have identified loci on chromosome 2, 14, and 16. However, the evidence is heterogeneous and limited. It seems that primary hyperhidrosis is polygenically inherited, and considering the impairment, further data to understand the genetic etiology of the disease are needed.

A11 Evaluation of phylogenetic inference methods to determine direction of HIV transmission

It has been postulated that the direction of HIV transmission between two individuals can be determined by phylogenetic analysis of HIV sequences. This approach may be problematic, since HIV sequences from newly infected individuals are often more similar to index sequences from samples collected years before transmission, compared to those from samples collected at the time of transmission. We evaluated the accuracy of phylogenetic methods for determining the direction of HIV transmission by analyzing next-generation sequencing (NGS) data from index–partner pairs enrolled in the HIV Prevention Trials Network (HPTN) 052 trial. HIV-infected index and HIV-uninfected partner participants were enrolled as serodiscordant couples; samples were analyzed from couples with index-to-partner HIV transmission that was confirmed by genetic linkage studies. NGS for HIV gp41 (HXB2 coordinates: 7691–8374) was performed using plasma samples from thirty-nine index–partner pairs (seventy-eight samples collected within 3 months of partner seroconversion). Maximum likelihood trees were generated using the entire dataset using FastTree v.2. Topological patterns of HIV from each index–partner pair were analyzed. The analysis included 9,368 consensus sequences and 521,145 total sequence reads for the seventy-eight samples analyzed. In 10 per cent (four out of thirty-nine) of couples, the phylogeny was inconsistent with the known direction of transmission. In 26 per cent (ten out of thirty-nine) of couples, the phylogeny results could not discern directionality. In 64 per cent (twenty-five out of thirty-nine) of couples, the results correctly indicated index-to-partner transmission; in two of these twenty-five cases, only one index sequence was closest to the most recent common ancestor. Phylogenetic analysis of NGS data obtained from samples collected within 3 months of transmission correctly determined the direction of transmission in 64 per cent of the cases analyzed. In 36 per cent of the cases, the phylogenetic topology did not support the known direction of infection, and in one-third of these cases the observed topology was opposite to the known direction of transmission. This demonstrates that phylogenetic topology alone may not be sufficient to accurately determine the direction of HIV transmission.

A High Prevalence Rate of Tibia Hemimelia in a Subregion of West Azarbaijan, Iran.

From 1995 to 2017 an abnormally high number of tibia hemimelia (TH) patients from the Maku subregion in the West Azarbaijan province of Iran were referred to our orthopedic department for treatment. Regarding the occurrence of TH in many families in a restricted region and negative results of available genetic tests, we hypothesized that a founder mutation etiology that is different from previous known genetic disorders might produce the trait of TH in our patients. Through a retrospective study, we collected demographic data including date of birth, patients and parents place of birth, sex, type of TH, presence of other musculoskeletal anomalies, and treatment from the patients who were referred to our department. We obtained a blood sample for genetic studies. We carried out genetic studies in cytogenetics and molecular levels on a patient with familial TH. The prevalence of TH in the Maku subregion of West Azarbaijan was 149.5 (95% confidence interval [CI]: 68.4-283.8) per 1 million live birth. The patients did not fit with any known syndromes with TH. Genetic evaluations of a patient with familial history of TH in this case series exhibited no detectable change in both cytogenetic and molecular levels. There was an obvious increased prevalence rate of TH in this province and particularly in the Maku subregion. The cytogenetic locations for known syndromic TH are not responsible for the observed anomalies in our patients. Our next step for detecting possible genetic mutations in our patients would be mutation analysis via very high-resolution whole genomic sequencing in more patients or genetic linkage study.

Resistance to ETEC F4/F18-mediated piglet diarrhoea: opening the gene black box.

Diarrhoea, a significant problem in pig rearing industry affecting pre- and post-weaning piglets is caused by enterotoxigenic Escherichia coli (ETEC). The ETEC are classified as per the fimbriae types which are responsible for bacterial attachment with enterocytes and release of toxins causing diarrhoea. However, genetic difference exists for susceptibility to ETEC infection in piglets. The different phenotypes found in pigs determine their (pigs') susceptibility or resistance towards fimbrial subtypes/variants (F4ab, F4ac, F4ad and F18). Specific receptors are present on intestinal epithelium for attachment of these fimbriae, which do not express to same level in all animals. This differential expression is genetically determined and thus their genetic causes (may be putative candidate gene or mutations) render some animals resistant or susceptible to one or more fimbrial subtypes. Genetic linkage studies have revealed the mapping location of the receptor loci for the two most frequent variants F4ab and F4ac to SSC13q41 (i.e. q arm of 13th chromosome of Sus scrofa). Some SNPs have been identified in mucin gene family, transferring receptor gene, fucosyltransferase 1 gene and swine leucocyte antigen locus that are proposed to be linked mutations for resistance/susceptibility towards ETEC diarrhoea. However, owing to the variety of fimbrial types and subtypes, it would be difficult to identify a single causative mutation and the candidate loci may involve more number of genes/regions. In this review, we focus on the genetic mutations in genes involved in imparting resistance/susceptibility to F4 or F18 ETEC diarrhoea and possibilities to use them as marker for selection against susceptible animals.

Moving beyond simple answers to complex disorders in sarcomeric cardiomyopathies: the role of integrated systems

The classic clinical definition of hypertrophic cardiomyopathy (HCM) as originally described by Teare is deceptively simple, "left ventricular hypertrophy in the absence of any identifiable cause." Longitudinal studies, however, including a seminal study performed by Frank and Braunwald in 1968, clearly described the disorder much as we know it today, a complex, progressive, and highly variable cardiomyopathy affecting ~ 1/500 individuals worldwide. Subsequent genetic linkage studies in the early 1990s identified mutations in virtually all of the protein components of the cardiac sarcomere as the primary molecular cause of HCM. In addition, a substantial proportion of inherited dilated cardiomyopathy (DCM) has also been linked to sarcomeric protein mutations. Despite our deep understanding of the overall function of the sarcomere as the primary driver of cardiac contractility, the ability to use genotype in patient management remains elusive. A persistent challenge in the field from both the biophysical and clinical standpoints is how to rigorously link high-resolution protein dynamics and mechanics to the long-term cardiovascular remodeling process that characterizes these complex disorders. In this review, we will explore the depth of the problem from both the standpoint of a multi-subunit, highly conserved and dynamic "machine" to the resultant clinical and structural human phenotype with an emphasis on new, integrative approaches that can be widely applied to identify both novel disease mechanisms and new therapeutic targets for these primary biophysical disorders of the cardiac sarcomere.

Linkage of DFNB1 to non-syndromic neurosensory autosomal-recessive deafness in Mediterranean families.

Recent studies show a susceptibility locus (DFNB1) responsible for non-syndromic neurosensory autosomal-recessive deafness (NSRD) mapping to the pericentromeric region of chromosome 13q. In order to better understand the frequency with which DFNB1 is the gene for deafness in our patient population and the role of DFNB1 in Caucasians, we performed a genetic linkage study with four microsatellite markers linked to DFNB1 in a total of 48 independent Mediterranean families, of which 30 and 18 were of Italian and Spanish descent, respectively. A maximum two-point lod score of 7.28 was found with marker D13S115 at a recombination frequency of theta 0.1. Significant lod scores were also obtained for D13S143, D13S292 and D13S175. Genetic heterogeneity was confirmed using the HOMOG program which indicated absence of linkage to DFNB1 in approximately 21% of the sample. This study clearly demonstrates that DFNB1 plays an important role in 79% of Mediterranean families with NSRD. Furthermore, results from multipoint analysis predict that the DFNB1 gene maps between markers D13S175 and D13S115 which are separated by approximately 14.2 cM.

ANMCO Position paper: New perspectives on the role of n-3 polyunsaturated fatty acids in cardiovascular prevention

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most important long-chain polyunsaturated fatty acids of the n-3 series (n-3 PUFA). Recent studies have clarified that EPA and DHA have different tissue distribution and influence target organs in a distinct way. In addition to the main effect of reducing triglycerides (TG), they exert antithrombotic, antiarrhythmic, anti-inflammatory, anti-atherogenic, and hemodynamic effects. The different action of PUFA n-3 depends on the dosage and duration of treatment: the effect on TG requires high doses and a few weeks/months of treatment.Several epidemiological studies have shown a relationship between hypertriglyceridemia and cardiovascular risk, confirmed by post-hoc analysis of statin trials and by recent genetic linkage studies. Moreover in secondary prevention, the evidence of a significant "residual risk", even in the presence of an adequate control of LDL-cholesterol, has led the scientific community to consider further intervention objectives in the context of the individual lipid profile, the most promising of which is certainly hypertriglyceridemia.The recent landmark REDUCE-IT study is the first major lipid intervention study to demonstrate a benefit deriving from an approach not based on the LDL target, focusing on a determinant factor of residual risk such as hypertriglyceridemia and treating it with high doses of n-3 PUFA (4 g/day).Overall, the "lipid residual risk" approach involves two integrated actions: (i) the achievement of the LDL-cholesterol target (<70 mg/dl) by using statins, ezetimibe, PCSK9 inhibitors; (ii) checking TG levels in order to start n-3 PUFA in case of TG values >150 mg/dl, at an initial dosage of 2-3 g/day (up to 4 g/day after 10-12 weeks).

Natural variation of chronological aging in the Saccharomyces cerevisiae species reveals diet-dependent mechanisms of life span control

Aging is a complex trait of broad scientific interest, especially because of its intrinsic link with common human diseases. Pioneering work on aging-related mechanisms has been made in Saccharomyces cerevisiae, mainly through the use of deletion collections isogenic to the S288c reference strain. In this study, using a recently published high-throughput approach, we quantified chronological life span (CLS) within a collection of 58 natural strains across seven different conditions. We observed a broad aging variability suggesting the implication of diverse genetic and environmental factors in chronological aging control. Two major Quantitative Trait Loci (QTLs) were identified within a biparental population obtained by crossing two natural isolates with contrasting aging behavior. Detection of these QTLs was dependent upon the nature and concentration of the carbon sources available for growth. In the first QTL, the RIM15 gene was identified as major regulator of aging under low glucose condition, lending further support to the importance of nutrient-sensing pathways in longevity control under calorie restriction. In the second QTL, we could show that the SER1 gene, encoding a conserved aminotransferase of the serine synthesis pathway not previously linked to aging, is causally associated with CLS regulation, especially under high glucose condition. These findings hint toward a new mechanism of life span control involving a trade-off between serine synthesis and aging, most likely through modulation of acetate and trehalose metabolism. More generally it shows that genetic linkage studies across natural strains represent a promising strategy to further unravel the molecular basis of aging.

Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors.

ObjectiveThe pathogenic mitochondrial DNA m.3243A>G mutation is associated with a wide range of clinical features, making disease prognosis extremely difficult to predict. We aimed to understand the cause of this heterogeneity.MethodsWe examined the phenotypic profile of 238 adult m.3243A>G carriers (patients and asymptomatic carriers) from the UK MRC Mitochondrial Disease Patient Cohort using the Newcastle Mitochondrial Disease Adult Scale. We modeled the role of risk factors for the development of specific phenotypes using proportional odds logistic regression. As mitochondria are under the dual control of their own and the nuclear genome, we examined the role of additive nuclear genetic factors in the development of these phenotypes within 46 pedigrees from the cohort.ResultsSeizures and stroke‐like episodes affect 25% and 17% of patients, respectively; more common features include hearing impairment, gastrointestinal disturbance, psychiatric involvement, and ataxia. Age, age‐adjusted blood heteroplasmy levels, and sex are poor predictors of phenotypic severity. Hearing impairment, diabetes, and encephalopathy show the strongest associations, but pseudo‐R 2 values are low (0.14–0.17). We found a high heritability estimate for psychiatric involvement (h 2=0.76, P = 0.0003) and moderate estimates for cognition (h 2=0.46, P = 0.0021), ataxia (h 2 = 0.45, P = 0.0011), migraine (h 2 = 0.41, P = 0.0138), and hearing impairment (h2 = 0.40, P = 0.0050).InterpretationOur results provide good evidence for the presence of nuclear genetic factors influencing clinical outcomes in m.3234A>G‐related disease, paving the way for future work identifying these through large‐scale genetic linkage and association studies, increasing our understanding of the pathogenicity of m.3243A>G and providing improved estimates of prognosis.

Genetic variation in sensitivity to estrogens and breast cancer risk.

Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens). This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling. Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in five different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol. Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density. The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.

Mouse models of SLC4-linked disorders of HCO3--transporter dysfunction.

The SLC4 family Cl-/[Formula: see text] cotransporters (NBCe1, NBCe2, NBCn1, and NBCn2) contribute to a variety of vital physiological processes including pH regulation and epithelial fluid secretion. Accordingly, their dysfunction can have devastating effects. Disorders such as epilepsy, hemolytic anemia, glaucoma, hearing loss, osteopetrosis, and renal tubular acidosis are all genetically linked to SLC4-family gene loci. This review summarizes how studies of Slc4-modified mice have enhanced our understanding of the etiology of SLC4-linked pathologies and the interpretation of genetic linkage studies. The review also surveys the novel disease signs exhibited by Slc4-modified mice which could either be considered to presage their description in humans, or to highlight interspecific differences. Finally, novel Slc4-modified mouse models are proposed, the study of which may further our understanding of the basis and treatment of SLC4-linked disorders of [Formula: see text]-transporter dysfunction.

Chapter 26 - The genetic landscape of Alzheimer disease

Alzheimer disease (AD), a progressive and neurodegenerative disease, is the most common form of dementia with high incidence in elderly people. Neuropathologically the disease is defined by the combined presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of phosphorylated tau protein. Genetically, the first clues were provided by genetic linkage studies that led to the identification of APP, PSEN1, and PSEN2 mutations as the main causes of autosomal-dominant early-onset AD. Another important hallmark was the identification of the APOE ɛ4 allele as a risk factor for late-onset AD. Over the last 20 years the development and implementation of new genetic and genomic technologies have allowed the identification of other genetic players in this disease. Genome-wide association studies identified more than 20 loci with common variability having small contributions to the susceptibility of AD. The majority of the genes mapped in these loci are known to be involved in specific biologic pathways: cholesterol metabolism, immune response, and endocytosis. More recently, the application of next-generation sequencing (mainly whole-exome sequencing) has begun to reveal the contribution of rarer variants with medium effects on risk for AD. This area of research has come a long way with many and important results allowing a better understanding of the disease. More efforts are still needed, however, to fully understand the etiology of this disease in order to establish reliable individual predictive models and put us closer to the development of a curative, preventive, or modulator drug.

Genetic linkage studies for the non‐geneticist

Genetic linkage studies for the non‐geneticist

Phenylethanolamine N-methyltransferase gene expression in PC12 cells exposed to intermittent hypoxia

Epidemiological studies show a strong correlation between Obstructive Sleep Apnea (OSA) and cardiovascular disorders. OSA patients experience intermittent hypoxia (IH), characterized by brief, but recurring episodes of cessation in breathing. These patients have higher levels of circulating catecholamines and an increased incidence of hypertension; however the mechanisms defining this association are not clearly established. Genetic linkage studies have associated the phenylethanolamine N-methyltransferase (PNMT) gene to the development of hypertension. PNMT, the terminal enzyme in the catecholamine biosynthetic pathway, directly responsible for adrenaline synthesis, is elevated in hypertensive animals. Recent studies utilizing PC12 cells show an increase in the expression of PNMT and its regulatory transcription factors when exposed to continuous hypoxia. The current study examined the regulation of PNMT under conditions of IH. The mRNA of PNMT was analyzed to assess if the regulation of PNMT expression entails alternative splicing. The mRNA and protein of transcription factors HIF1α, Egr-1, GR, and Sp1, were analyzed to assess the cellular pathways involved in regulating PNMT expression. A PNMT promoter-driven luciferase assay was performed to evaluate promoter activity under IH. Preliminary results lay an antecedent for the regulation of PNMT by IH conceivably via an altered regulation of its transcription factors and establish a possible role for PNMT in IH mediated hypertension in OSA patients.

Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case-Control Study.

Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering. Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancer-free controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided. First- and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001; HR = 1.04, 95% CI = 1.02 to 1.07, P = .001) and urothelial cancer (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001; HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), cervical (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01), and lung cancer (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR = 1.35, 95% CI = 1.2 to 1.5, P < .001) and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02). Spouses showed an increased risk for laryngeal (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) and cervical cancer (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007). These results did not substantively change after correction for suspected smoking behaviors. Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies.

Bradford C. Berk: Picking Good Questions.

As Brad Berk sees it, “All the work I do can pretty much fit under the heading of signal transduction in blood vessels.” This deceptively short phrase, however, covers decades of research into the cellular and genetic mechanisms that produce some of cardiovascular medicine’s most stubborn challenges: atherosclerosis, aneurysms, and pulmonary hypertension. Berk’s academic career has led him from the University of Rochester to Harvard Medical School, Emory University, and the University of Washington before circling back to Rochester. Currently, he holds the post of Distinguished University Professor in medicine, neurology, pathology, and pharmacology and physiology. He has founded and directed 2 multidepartment institutes: the Aab Cardiovascular Research Institute (CVRI; from 1999 to 2006) and the University of Rochester Neurorestoration Institute (URNI; from 2015 to the present). Bradford C. Berk While at the University of Washington, in 1998, he published with Oren Traub a review1 of what was then known about how changes in blood-flow profile (steady versus disturbed) influence vascular disease. Berk went on to develop a highly reproducible model2 for vascular remodeling of the carotid as mediated by blood-flow profile. The disturbed flow region shows the formation of intima—a pathological thickening of the vessel wall. Because this thickening is predictive for cardiovascular events, the identification of genetic factors that played a role in the process3 marked a significant advance in cardiovascular research. Together with Korshunov et al, Berk studied 3 disease processes that contribute to intima: endothelial dysfunction, inflammation, and smooth muscle growth. By performing a genetic linkage study to home in on regions of the mouse genome that contribute to the intima,4 Berk and Korshunov identified a specific gene ( RpL17 ) that accounts for smooth muscle cell growth. With Smolock et al,5,6 they found a key link to inflammation now identified …

An Unbiased Linkage Approach Reveals That the p53 Pathway Is Coupled to NK Cell Maturation.

Natural killer cells constitute potent innate lymphoid cells that play a major role in both tumor immunosurveillance and viral clearance via their effector functions. A four-stage model of NK cell functional maturation has been established according to the expression of CD11b and CD27, separating mature NK (mNK) cells into distinct populations that exhibit specific phenotypic and functional properties. To identify genetic factors involved in the regulation of NK cell functional maturation, we performed a linkage analysis on F2 (B6.Rag1-/- × NOD.Rag1-/- intercross) mice. We identified six loci on chromosomes 2, 4, 7, 10, 11, and 18 that were linked to one or more mNK cell subsets. Subsequently, we performed an in silico analysis exploiting mNK cell subset microarray data, highlighting various genes and microRNAs as potential regulators of the functional maturation of NK cells. Together, the combination of our unbiased genetic linkage study and the in silico analysis positions genes known to affect NK cell biology along the specific stages of NK cell functional maturation. Moreover, this approach allowed us to uncover a novel candidate gene in the regulation of NK cell maturation, namely Trp53 Using mice deficient for Trp53, we confirm that this tumor suppressor regulates NK cell functional maturation. Additional candidate genes revealed in this study may eventually serve as targets for the modulation of NK cell functional maturation to potentiate both tumor immunosurveillance and viral clearance.

Genetic Insights Into Bicuspid Aortic Valve Disease

Bicuspid aortic valve (BAV) is the most common valvular congenital heart defect in the general population. BAV is commonly associated with the presence of other congenital cardiovascular malformations, which leads to cardiovascular complications requiring surgery in around 27% of cases. Familial clustering of BAV is well-recognized, and international guidelines advocate that first-degree relatives of patients with BAV be screened. Studies of genetic linkage in affected families, syndromic forms of BAV, and sporadic patients led to discoveries of genetic loci harboring genes involved in the development of BAV. However, only a few of these findings have been replicated in other populations and been proven functional in animal models. This task is further complicated by the phenotypic and genetic heterogeneity of BAV disease. BAV differs in valve fusion patterns and some studies have suggested that different valve fusion patterns originate from different pathophysiological processes. We present an overview of the published work on genetic linkage and its association with BAV disease. Presented articles used different discovery strategies ranging from candidate gene association to whole exome sequencing, as well as various validation protocols. Although still very limited, our understanding of the molecular pathology of BAV disease is likely to influence current clinical practice by enabling genetic counseling, prenatal diagnosis, and risk stratification for individual patients. This task will be made possible thanks to increasing availability, as well as the reduced cost of next-generation sequencing and bioinformatic processing of data.

Genetics of alcohol use disorder

Contrary to the stigmatizing perception, alcohol dependence is not a mark of moral decay, but the result of combining environmental, social, cultural and especially biological factors, family studies finding that about 50% of the risk is due to heredity. Genetic linkage and association studies have failed to identify significant risk alleles, except for the alcohol-metabolizing enzyme genes. Thus, a new approach was needed - genome wide association studies (GWAS) that do not depend on a pre-existing hypothesis and highlighted new polymorphisms associated with susceptibility to alcoholism. A review of family, twin, linkage, candidate genes and GWAS will be briefly presented.