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PubMed2001

Inherited genetic susceptibility to breast cancer.

Inherited genetic susceptibility to breast cancer can be due both to genes which confer a high degree of risk and to polygenes which have a smaller effect on disease risk. An estimated 5-10% of breast cancer is considered to be due to mutations in genes conferring high risk which results in hereditary patterns of disease. Two major breast cancer susceptibility genes, BRCA1 and BRCA2, which were identified using linkage analysis in large extended breast and/or ovarian cancer pedigrees, are estimated to account for the majority of large families with breast/ovarian cancer predisposition and about two-thirds of large breast cancer families. The associated lifetime risk for breast cancer in mutation carriers ranges from 40% to 90%, depending on the extent of family history and the population. Other genetic factors, such as HRAS or CAG repeats of AR, as well as reproductive and hormonal factors may therefore modify cancer risk. Women at particularly high risk of developing breast cancer represent a group in whom expensive and rigorous screening programmes are cost-effective and who may benefit from trials of chemoprevention. There are only preliminary data on the efficacy of increased surveillance and on risk reduction due to prophylactic surgery. However, for chemoprevention to be equivalent to prophylactic mastectomy, it will be necessary to strive for an equivalent reduction. The efficacy of chemoprevention in this high-risk population is unknown. Existing and new agents for chemoprevention need to be carefully assessed in properly designed clinical trials among such women. In the process, other factors modifying the penetrance in mutation carriers need to be taken into account in order to evaluate the true effect of the chemopreventive agents. Polygenes confer much lower levels of risk and may be relevant for risk assessment when the effects of multiple loci, possibly in conjunction with environmental factors, are understood and quantified. At present, it seems unlikely that the genetic information at single polygenes will be clinically relevant for risk assessment and management.

Biomarkers, Tumor↗
PubMedDate not supplied

Marker assisted selection for the improvement of two antagonistic traits under mixed inheritance.

A Monte Carlo simulation was used to investigate the potential of Marker Assisted Selection (MAS) in a multiple-trait situation. Only additive effects were considered. The base population was assumed to be in linkage equilibrium and, next, the population was managed over 15 discrete generations, 10 males and 50 females were chosen out of the 100 candidates of each sex. Performance for two traits was simulated with an overall heritability of a given trait equal to 0.25 or 0.10 and the overall genetic correlation between traits was generally equal to -0.4 except in one case where it was equal to 0. The model involved one biallelic QTL, accounting for 10 or 20% of the genetic variance of a given trait, plus polygenes. Initial allelic frequencies at the QTL, were generally equal to 0.5 but in one case were equal to 0.1 and 0.9. A marker with 120 different alleles in the 60 founder parents was simulated in the vicinity of the QTL. Two values of the recombination rate between these two loci were considered, 0.10 and 0.02. The genetic evaluation was based on a multiple-trait BLUP animal model, accounting (MAS) or not (conventional BLUP) for marker information. Two sets of simulations were run: (1) a "missing data" case, with males having no record for one of the traits, and (2) a "secondary trait" case, with one trait having a weight in the aggregate genotype 4 times less than the other trait and the QTL acting only on this secondary trait. In the first set, evaluation methods were found to mainly affect the accuracy of overall genetic values prediction for the trait with missing data. In comparison with BLUP, MAS led to an extra overall genetic response for the trait with missing data, which was strongly penalised under the conventional BLUP, and to a deficit in response for the other trait. This more balanced evolution of the two traits was obtained, however, at the expense of the long-term overall cumulated response for the aggregate genotype, which was 1 to 2.5% lower than the one obtained under the conventional BLUP. In the second set of simulation, in the case of low initial frequency (0.1) of the QTL allele favourable to the secondary trait, MAS was found to be substantially more efficient to avoid losing this allele than BLUP only when the QTL had a large effect and the marker was close. More benefits should be expected from MAS with more specific applications,such as early selection of animals, or by applying dynamic procedures i.e. letting the respective weights to QTL and polygenic values in the selection criterion vary across generation.

Animals↗
PubMed2007

Complex trait genetics of refractive error.

Refractive errors (myopia, hyperopia, and astigmatism) are complex heterogeneous disorders of the human eye and are ideal for genetic investigation. Moderate to severe refractive errors can predispose individuals to poor visual development, various types of glaucoma, misshapen corneal surfaces, premature cataracts, and loss of retinal integrity, which can lead to detachment. Knowledge of genetic mechanisms involved in refractive error susceptibility may allow treatment to prevent progression or to further examine gene-environment interactions. Early genetic predisposition detection for developing severe refractive errors may be useful for efficient and cost-effective screening program design. This review explores the genetic mechanisms associated with nonsyndromic refractive error development known to date.

Animals↗
PubMed2025

Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events.

IMPORTANCE: Peripheral artery disease (PAD) is a heritable atherosclerotic condition associated with functional decline and high risk for limb loss. With growing knowledge of the genetic basis for PAD and related risk factors, there is potential opportunity to identify individuals at high risk using polygenic risk scores (PRSs). OBJECTIVE: To develop a novel integrated, multiancestry polygenic score for PAD (PRS-PAD) and evaluate its risk estimation for PAD and major adverse limb events in 3 populations. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study was conducted among individuals with genotyping and electronic health record data in the UK Biobank (2006-2021), All of Us (AoU, 2018-2022), and the Mass General Brigham Biobank (MGBB, 2010-2023). Data were analyzed from July 2023 to February 2025. EXPOSURES: PRS-PAD, previously published PAD polygenic scores, and clinical risk factors. MAIN OUTCOMES AND MEASURES: The primary outcomes were PAD and major adverse limb events, defined as a surrogate of major amputation and acute limb ischemia. RESULTS: The study populations included 400&#x202f;533 individuals from the UK Biobank (median [IQR] age, 58.2 [45.0-71.4] years; 216&#x202f;215 female participants [53.9%]), 218&#x202f;500 from AoU (median [IQR] age, 53.6 [37.7-65.0] years; 132&#x202f;647 female participants [60.7%]), and 32&#x202f;982 from MGBB (median [IQR] age, 56.0 [32.0-80.0] years; 18&#x202f;277 female participants [55.4%]). In the UK Biobank validation cohort, PRS-PAD was associated with an odds ratio [OR] per SD increase of 1.63 (95% CI, 1.60-1.68; P&#x2009;<&#x2009;.001). After adjusting for clinical risk factors, the OR for the top 20% of PRS-PAD was 1.68 (95% CI, 1.62-1.74; P&#x2009;<&#x2009;.001) compared to the remainder of the population. Among PAD cases without a history of diabetes, smoking, or chronic kidney disease (n&#x2009;=&#x2009;3645), 1097 individuals (30.1%) had a high PRS-PAD (top 20%). In incident disease analysis, PRS-PAD improved discrimination (C statistic, 0.761), which was nearly equivalent to the performances of diabetes (C statistic, 0.760) and smoking (C statistic, 0.765). Among individuals with prevalent PAD, high PRS-PAD was associated with an increased risk of incident major adverse limb events in the UK Biobank (hazard ratio [HR], 1.75; 95% CI, 1.18-2.57; P&#x2009;=&#x2009;.005), MGBB (HR, 1.56; 95% CI, 1.06-2.30; P&#x2009;=&#x2009;.02), and AoU (HR, 1.57; 95% CI, 1.06-2.33; P&#x2009;=&#x2009;.03). CONCLUSIONS AND RELEVANCE: This cohort study develops a new PRS that stratifies risk of PAD and adverse limb outcomes. Incorporating polygenic risk into PAD care warrants further investigation to guide screening and tailor management to prevent major adverse limb events.

Humans↗
PubMed2025

Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.

IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n&#x2009;=&#x2009;42&#x202f;137, 2008-2025), with replication in the UK Biobank (n&#x2009;=&#x2009;295&#x202f;160, 2005-2010), FinnGen (n&#x2009;=&#x2009;417&#x202f;950, 2017-2025), and the Veterans Affairs Million Veteran Program (n&#x2009;=&#x2009;516&#x202f;066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors. EXPOSURES: DCM polygenic risk score and DCM monogenic variants. MAIN OUTCOMES AND MEASURES: The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy. RESULTS: The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24&#x202f;551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P&#x2009;<&#x2009;.001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors. CONCLUSIONS AND RELEVANCE: In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.

Humans↗
PubMed2025

Polygenic Contributions to Lithium Augmentation Outcomes in Unipolar Depression.

IMPORTANCE: Lithium augmentation is an effective treatment for patients with major depression after inadequate antidepressant response, but therapeutic outcomes vary considerably between individuals. Molecular studies may provide novel insights into treatment prediction and guide personalized therapy. OBJECTIVE: To investigate the association of polygenic risk scores (PRS) for schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) with clinical outcomes after lithium augmentation. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed prospectively assessed treatment outcomes in patients who underwent lithium augmentation. Disorder-specific PRS were calculated using well-powered genome-wide association study summary statistics. Participants were recruited from 13 psychiatric hospitals, primarily in the greater Berlin area, between 2008 and 2020. They were patients with MDD who showed inadequate response to at least 1 antidepressant, a baseline score of 12 or more on the 17-item Hamilton Depression Rating Scale (HAMD-17), adequate treatment duration (&#x2265;4 weeks), and no diagnostic or co-medication changes. Data analysis was conducted between June 2022 and November 2023. EXPOSURE: Polygenic risk scores for MDD, SCZ, or BIP. MAIN OUTCOMES AND MEASURES: Response was defined as a 50% or greater reduction in HAMD-17 score, remission as a HAMD-17 score of 7 or less. Cox proportional hazards models, adjusted for ancestry, demographic, and clinical covariates, were used to estimate hazard ratios (HRs) for favorable outcomes. RESULTS: Among 193 patients (mean [SD] age, 49.5 [13.4] years; 118 [61.1%] female and 75 [38.9%] male), higher BIP-PRS were associated with both response (HR, 1.29; 95% CI, 1.02-1.63; P&#x2009;=&#x2009;.03) and remission (HR, 1.52; 95% CI, 1.14-2.04; P&#x2009;=&#x2009;.004), explaining 2.51% and 4.53% of the variability in treatment outcomes, respectively. Individuals in the highest tertile of the BIP-PRS distribution had a 2.02-fold (95% CI, 1.15-3.53) higher likelihood of response and a 2.26-fold (95% CI, 1.17-4.36) higher chance of remission compared with those in the lowest tertile. Additionally, lower MDD-PRS was associated with better response to lithium augmentation (HR, 0.81; 95% CI, 0.66-1.00; P&#x2009;=&#x2009;.048; Nagelkerke R2&#x2009;=&#x2009;1.99%). No significant associations were observed between SCZ-PRS and response (HR, 1.00; 95% CI, 0.80-1.24; P&#x2009;=&#x2009;.97) or remission (HR, 1.12; 95% CI, 0.85-1.48; P&#x2009;=&#x2009;.42). CONCLUSIONS AND RELEVANCE: Individuals carrying a higher polygenic burden for BIP and lower polygenic risk for MDD are more likely to benefit from lithium augmentation. Our findings suggest that disease-related PRS may aid in developing treatment prediction models for lithium augmentation response in depression, potentially informing clinical decision-making.

Humans↗
PubMed1999

Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores.

Obsessive-compulsive disorder (OCD) is a complex psychiatric disorder characterized by recurring obsessions or compulsions that cause significant distress to the patient or significantly interfere with the patient's normal home, work, or social activities [Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC: American Psychiatric Association, 1994]. Twin and family studies have suggested that OCD has a significant genetic component. We performed complex segregation analyses using POINTER with families ascertained through an OCD-affected proband. In an attempt to resolve the phenotypic heterogeneity observed among individuals with OCD these segregation analyses used four factor-analytic symptom dimensions to subset the family sample based upon probands' symptom factor scores. Analysis of the entire sample allowed rejection of only the no transmission model; that model was also rejected in all subsequent analyses. Limiting the analyses to families with at least one OCD-affected member in addition to the proband (the demonstrably familial form of OCD) allowed rejection of all models except the mixed model. Analyses limited to families of high-factor-3 (symmetry and ordering symptoms) probands led to rejection of the polygenic model, indicating the involvement of a major locus. Additionally, the relative risk of OCD or subclinical OCD was 1.7 for relatives of probands with a factor 3 score greater than zero compared with relatives of probands with a low factor score. The symptoms attributed to high factor 3 scores (symmetry and ordering) may constitute a genetically significant symptomatic subtype of OCD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:669-675, 1999.

Aging↗
PubMed2000

Linkage and associated studies of schizophrenia.

Genetic epidemiology has provided consistent evidence over many years that schizophrenia has a genetic component, and that this genetic component is complex, polygenic, and involves epistatic interaction between loci. Molecular genetics studies have, however, so far failed to identify any DNA variant that can be demonstrated to contribute to either liability to schizophrenia or to any identifiable part of the underlying pathology. Replication studies of positive findings have been difficult to interpret for a variety of reasons. First, few have reproduced the initial findings, which may be due either to random variation between two samples in the genetic inputs involved, or to a lack of power to replicate an effect at a given alpha level. Where positive data have been found in replication studies, the positioning of the locus has been unreliable, leading no closer to positional cloning of genes involved. However, an assessment of all the linkage studies performed over the past ten years does suggest a number of regions where positive results are found numerous times. These include regions on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 18, 22 and the X. All of these data are critically reviewed and their locations compared. Reasons for the difficulty in obtaining consistent results and possible strategies for overcoming them are discussed. Am. J. Med. Genet. (Semin. Med. Genet.) 97:23-44, 2000.

Chromosome Mapping↗
PubMed1998

Susceptibility to tuberculosis as a complex genetic trait: analysis using recombinant congenic strains of mice.

Previous advances in the genetics of infectious diseases derived principally from identification of single genes and their isolated effects on the progression of infection. Modern genetic analysis represents a powerful means of understanding the interplay among different pathways activated in the course of infection, their hierarchy and interactions in terms of the development of an optimal protective strategy. By utilizing both whole-genome scanning of (C3HxC57BL/6)F2 and a set of the recombinant congenic strains, produced by backcrossing B10 onto a C3H background, we demonstrated that susceptibility to tuberculosis is a multigenic trait. We have identified two distinct groups of susceptible mice: one that dies within four to six weeks of infection (supersusceptible) and another that dies within seven to 10 weeks (comparable to the susceptible parental strain). Our preliminary genetic analysis suggests that the susceptibilty of those groups is controlled by different genetic factors. Supersusceptible mice exhibit dramatic lung pathology, not observed in either parental strain, and their survival after infection with virulent Mycobacterium tuberculosis is comparable to that of mice rendered immunodeficient by disruption of essential immune genes. Further genetic and functional analyses of these strains offer possibilities for understanding the control of transmission, preferential growth of the pathogen in the lung, and mechanisms of local and systemic protective immune responses.

Animals↗
PubMed2024

Polygenic liability for anxiety in association with comorbid anxiety in multiple sclerosis.

OBJECTIVE: Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS. METHODS: Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression. RESULTS: A total of 71,343 individuals of European genetic ancestry were used: Canada (n&#x2009;=&#x2009;334; 212 MS), UK Biobank (n&#x2009;=&#x2009;70,431; 1,390 MS), and the USA (n&#x2009;=&#x2009;578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease. INTERPRETATION: Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.

Humans↗
PubMed2002

Interplay between heredity and environment in the recent explosion of type 1 childhood diabetes mellitus.

The fast increase in the incidence of childhood type 1 diabetes mellitus (T1DM) that cannot be explained by changes in the genetic susceptibility, led us to look for environmental causes. To test the hypothesis that the initiation of the autoimmune process of childhood T1DM in genetically susceptible subjects begins in the perinatal period by a viral infection, we studied the seasonal variations in the month of birth of several cohorts of patients compared to the general population. Population groups with high or low T1DM incidence were analyzed separately by t-test and the Cosinor methods. In areas with populations with a high incidence (Israeli Jews, Sicily, Sardinia, Slovenia, Germany) we found that the children (in Sicily also young adults) who subsequently developed T1DM, have a higher incidence of births in the summer months than in other seasons of the year, a mirror image of the seasonality of the clinical onset of disease. This pattern differed significantly from the seasonality of the total live births in the same populations. In populations with a low T1DM incidence, (China, Japan and Cuba) no seasonality of month of birth was found. Similar findings have been reported, from five counties in the U.K. and the Netherlands. It is hypothesized that mothers who become pregnant during the period of yearly viral epidemics transmit to the fetus, either a virus or antiviral antibodies, which determine whether an autoimmune process against the pancreatic beta is initiated or whether the fetus is protected against that process.

Diabetes Mellitus, Type 1↗
PubMed2002

Impact of genetic and non-genetic factors in type 1 diabetes.

Type 1 insulin-dependent diabetes is due to destruction of the insulin secreting cells of the islets of Langerhans. The disease is caused by non-genetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These unknown environmental factors may operate over a limited period either in early or later and to a variable degree, playing a particularly substantial role in adults. The environment then induces an immune process associated with destruction of the islet beta cell that can be detected in early life and persists up to disease onset. Apart from an association with the insulin gene there is no evidence that genes associated with type 1 diabetes, including HLA and CTLA4 influence the targeting of the immune response to the insulin-secreting cells. The critical period of immune activation is probably short and the process leading to diabetes probably has a long prodrome but of variable duration that determines the age at presentation with clinical disease. The amplification both of this immune response and the destructive process is in part genetically determined, involving HLA genes. The clinical spectrum of the disease process associated with type 1 diabetes is wide, encompassing insulin-dependence, non-insulin dependence and even transient impaired glucose tolerance. Type 1 diabetes presenting in adults, in contrast to children, is predominantly determined by non-genetic factors with a reduced role for protective and susceptibility HLA alleles. Thus, the evidence is that genes involved in genetic susceptibility to type 1 diabetes operate predominantly in children not adults and in both amplify the immune response and the rate of disease progression.

Diabetes Mellitus, Type 1↗
PubMed2002

Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes.

More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype-Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status-in about 85% of cases with pancreatic insufficiency and in about 15% of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in beta-defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in alpha-1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products.

Animals↗
PubMed1992

Familial intestinal malrotation with midgut volvulus and facial anomalies: a disorder involving a gene controlling the normal gut rotation?

We report on 2 sisters with congenital midgut volvulus. Both had similar facial changes different from those of their parents and the other 2 unaffected sibs. Both parents had normal barium meal roentgenograms. The occurrence of these abnormalities in sibs born to parents with apparently normal gastrointestinal tract anatomy suggest autosomal recessive inheritance, although a coincidence, multifactorial or autosomal dominant inheritance with nonpenetrance in either of the parents cannot be excluded.

Abnormalities, Multiple↗
PubMed2003

A genome-wide scan for loci predisposing to non-syndromic cleft lip with or without cleft palate in two large Syrian families.

Non-syndromic cleft lip with/without cleft palate (CL/P) is a common, usually non-fatal birth defect of complex etiology. Several segregation analyses have demonstrated that genetic factors are important in the pathogenesis of CL/P, most likely through the interaction of several genes of modest effects. The aim of this study was to perform a genome-wide linkage analysis to identify/search for candidate gene loci for CL/P. We conducted a genome-wide search in two large, relatively isolated Syrian families, each one with a large number of cases with CL/P (18 in family 1 and 4 in family 2). A locus with a multipoint LOD score of 2.80 and a 2-point non-parametric MLS LOD of 3.0 was detected on 17p13.1. Other chromosomal regions with multipoint LOD scores > or = 1.2 (P < or = 0.01) included 3p21.2, 4q32.1, and 7q34. These data indicate the possible presence of several susceptibility loci for CL/P and identify a strong candidate locus for this common birth defect on chromosome 17p13.

Chromosome Mapping↗
PubMed2002

Alcohol and genetics: new models.

Alcoholism is a complex genetic trait; susceptibility is influenced by multiple genes of small effect. To pursue mechanistic studies, genetic animal models have been used. These models are partial, each addressing one or more of the contributing traits rather than the disease as a whole. Animal studies have modeled alcohol's rewarding effects, the development of tolerance, the pathological consequences to brain systems, and the dependence on alcohol inferred from the presence of withdrawal symptoms when the drug is removed. The classical genetic methods of inbred strain analysis and development and studies of selectively bred lines have been employed for more than 40 years. Recently, such studies have shown that a genetic tendency to experience severe withdrawal is associated with a tendency to avoid self-administration of alcohol. Also recently, attempts to identify the specific genes conferring risk or protection from alcohol's effects have been undertaken. These studies have used mapping techniques based on gene sequence polymorphisms, studies of gene expression differences, and the use of candidate gene targeting such as creation of null mutants. Studies reviewed here have mapped quantitative trait loci (QTL) for many genes affecting alcohol sensitivity, tolerance, reward, and withdrawal severity. The furthest progress in gene mapping has been made toward one withdrawal QTL on mouse chromosome 4. Using multiple congenic strains, the gene conferring increased withdrawal severity has been isolated to a region of less than 1 centiMorgan, containing fewer than 20 genes. A strong candidate gene, coding for a multiple PS095/DLG/Z0-1 (PDZ) binding domain zinc finger protein, cannot be excluded. Although many more such genes will be identified in the near future, their contribution to the mapped phenotype will be shown to be dependent on epistatic interactions with other risk genes, as well as genes in the animal's background. Progress in gene identification will also depend crucially on the precise description of the phenotypes being mapped so that their pleiotropic range of influence on the multi-behavioral phenotypic syndrome can be determined.

Alcoholism↗