Gene Identification Efforts Research Articles

Systematic review and meta-analysis of the screening and identification of key genes in gastric cancer using DNA microarray database

OBJECTIVE: A comprehensive evaluation of studies using DNA microarray datasets for screening and identifying key genes in gastric cancer is the goal of this systematic review and meta-analysis. To better understand the molecular environment associated with stomach cancer, this study aims to provide a quantitative synthesis of findings. PURPOSE: Using DNA microarray databases in a systematic manner, this study aims to analyze gastric cancer (GC) screening and gene identification efforts. Through a literature review spanning 2002–2022, this research aims to identify key genes associated with GC and develop strategies for screening and prognosis based on these findings. METHODS: The following databases were searched extensively: Science Direct, NCKI, Web of Science, Springer, and PubMed. Fifteen studies met the inclusion and exclusion criteria; 10,134 tissues served as controls and 11,724 as GCs. The levels of critical genes, including COL1A1, COL1A2, THBS2, SPP1, SPARC, COL6A3, and COL3A1, were compared in normal and GC tissues. Rev Man 5.3 was used to do the meta-analysis. While applying models with fixed or random effects, 95% confidence intervals and weighted mean differences were computed. RESULTS According to the meta-analysis, GC tissues exhibited substantially elevated levels of important genes when contrasted with the control group. In particular, there were statistically significant increases in COL1A1 (MD = 2.43, 95% CI: 1.84–3.02), COL1A2 (MD = 2.75, 95% CI: 1.09–4.41), THBS2 (MD = 2.54, 95% CI: 1.66–3.41), SPP1 (MD = 3.64, 95% CI: 3.40–3.88), SPARC (MD = 1.57, 95% CI: 0.37–2.77), COL6A3 (MD = 2.31, 95% CI: 2.02–2.60), and COL3A1 (MD = 2.21, 95% CI: 1.59–2.82). CONCLUSIONS: The COL1A1, THBS2, SPP1, COL6A3, and COL3A1 genes were shown to have potential use in germ cell cancer screening and prognosis, according to this research. Clinical assessment and prognosis of heart failure patients may be theoretically supported by the results of this study.

Evaluating the impact of a new educational tool on understanding of polygenic risk scores for alcohol use disorder.

As gene identification efforts have advanced in psychiatry, so have aspirations to use genome-wide polygenic information for prevention and intervention. Although polygenic risk scores (PRS) for substance use and psychiatric outcomes are not yet available in clinical settings, individuals can access their PRS through online direct-to-consumer resources. One of these widely used websites reports that alcohol use disorder is the third most requested PRS out of >1,000 conditions. However, data indicate that there are misunderstandings about complex genetic concepts, with a lower understanding of PRS being associated with a more negative impact of receiving polygenic risk information. There is a need to develop and evaluate educational tools to increase understanding of PRS. We conducted a randomized controlled trial to evaluate the impact of web-based educational information on understanding of PRS for alcohol use disorder. A total of 325 college students (70.4% female; 43.6% White; mean age = 18.9 years) from an urban, diverse university completed the study. Overall, participants were highly satisfied with the educational information. Results from a one-way ANOVA indicated that there was a significant increase in overall understanding of PRS for alcohol use disorder (p-value < 0.001), among individuals who received educational information about PRS and alcohol use disorder, as compared to receiving no accompanying information (adj. p-value < 0.001), or educational information about alcohol use disorder only (adj. p-value < 0.001). These findings suggest that the web-based educational tool could be provided alongside polygenic risk information in order to enhance understanding and interpretation of the information. [ClinicalTrials.gov], identifier [NCT05143073].

Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions.

Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined. Using data from Swedish national registries for a cohort born from 1932 to 1970 (N=1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A=0.32) and men (A=0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities.

Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease. In some cases, identification of the precise genetic defect and/or the downstream pathological consequences of disease mutations have yielded promising therapeutic opportunities. In this review, we discuss evidence for pathogenic overlap among multiple forms of inherited neuropathy, highlighting genetic defects in axonal transport, mitochondrial dynamics, organelle-organelle contacts, and local axonal protein translation as recurrent pathological processes in inherited axonal neuropathies. We also discuss how these insights have informed emerging treatment strategies, including specific approaches for single forms of neuropathy, as well as more general approaches that have the potential to treat multiple types of neuropathy. Such therapeutic opportunities, made possible by improved understanding of molecular and cellular pathogenesis and advances in gene therapy technologies, herald a new and exciting phase in inherited peripheral neuropathy.

Genetic syndromes with diabetes: A systematic review.

Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.

On the Genetic and Environmental Relationship Between Suicide Attempt and Death by Suicide.

The authors examined the extent to which the genetic and environmental etiology of suicide attempt and suicide death is shared or unique. The authors used Swedish national registry data for a large cohort of twins, full siblings, and half siblings (N=1,314,990) born between 1960 and 1990 and followed through 2015. They conducted twin-family modeling of suicide attempt and suicide death to estimate heritability for each outcome, along with genetic and environmental correlations between them. They further assessed the relationship between suicide attempt by young people compared with adults. In bivariate models, suicide attempt and death were moderately heritable among both women (attempt: additive genetic variance component [A]=0.52, 95% CI=0.44, 0.56; death: A=0.45, 95% CI=0.39, 0.59) and men (attempt: A=0.41, 95% CI=0.38, 0.49; death: A=0.44, 95% CI=0.43, 0.44). The outcomes were substantially, but incompletely, genetically correlated (women: rA=0.67, 95% CI=0.55, 0.67; men: rA=0.74, 95% CI=0.63, 0.87). Environmental correlations were weaker (women: rE=0.36, 95% CI=0.29, 0.45; men: rE=0.21, 95% CI=0.19, 0.27). Heritability of suicide attempt was stronger among people ages 10-24 (A=0.55-0.62) than among those age 25 and older (A=0.36-0.38), and the genetic correlation between attempt during youth and during adulthood was stronger for women (rA=0.79, 95% CI=0.72, 0.79) than for men (rA=0.39, 95% CI=0.26, 0.47). The genetic and environmental etiologies of suicide attempt and death are partially overlapping, exhibit modest sex differences, and shift across the life course. These differences must be considered when developing prevention efforts and risk prediction algorithms. Where feasible, suicide attempt and death should be considered separately rather than collapsed, including in the context of gene identification efforts.

Genetic and Social-Environmental Influences on Substance Use and Disorders

The past decade has brought large gains in our understanding of the genetic basis of substance use and related disorders. Gene identification efforts have underscored the highly polygenic nature of substance use behaviors, prompting the development of novel methods for indexing risk from molecular genetic data, such as polygenic approaches to characterize aggregate measured genetic risk. Genetic risk for substance use disorders also varies as a function of the social environment: risky environmental exposures (eg, adverse events) amplify the effects of genetic risk, whereas protective or low-risk environmental exposures minimize the effects of genetic risk. As we move toward a precision medicine model wherein genetic variation can potentially guide personalized treatment plans, it is paramount that we draw upon polygenic methods—consider the powerful role of the social environment in shaping risk for substance use disorders—and incorporate psychosocial treatments that complement pharmacological therapeutic plans. [ Psychiatr Ann . 2021;51(4):170–174.]

The Genetics of Externalizing Problems.

Externalizing problems generally refer to a constellation of behaviors and/or disorders characterized by impulsive action and behavioral disinhibition. Phenotypes on the externalizing spectrum include psychiatric disorders, nonclinical behaviors, and personality characteristics (e.g. alcohol use disorders, other illicit substance use, antisocial behaviors, risky sex, sensation seeking, among others). Research using genetic designs including latent designs from twin and family data and more recent designs using genome-wide data reveal that these behaviors and problems are genetically influenced and largely share a common genetic etiology. Large-scale gene-identification efforts have started to identify robust associations between genetic variants and these phenotypes. However, there is still considerable work to be done. This chapter provides an overview of the current state of research into the genetics of behaviors and disorders on the externalizing spectrum.

Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported. We conducted a meta-analysis of 2 population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)-based heritability and conducted a series of secondary aggregate genetic analyses. No individual locus reached genome-wide significance. Gene and set based analyses, both overall and using tissue-specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta-analysis of SNP-based heritability resulted in a modest estimate of =0.19 (SE=0.10), though this was driven by 1 sample (N=3,683, =0.36, SE=0.14, p=0.04). No significant genetic correlations with other relevant outcomes were observed. Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings.

Examining interactions between genetic risk for alcohol problems, peer deviance, and interpersonal traumatic events on trajectories of alcohol use disorder symptoms among African American college students.

Numerous studies have demonstrated that genetic and environmental factors interact to influence alcohol problems. Yet prior research has primarily focused on samples of European descent and little is known about gene-environment interactions in relation to alcohol problems in non-European populations. In this study, we examined whether and how genetic risk for alcohol problems and peer deviance and interpersonal traumatic events independently and interactively influence trajectories of alcohol use disorder symptoms in a sample of African American students across the college years (N = 1,119; Mage = 18.44 years). Data were drawn from the Spit for Science study where participants completed multiple online surveys throughout college and provided a saliva sample for genotyping. Multilevel growth curve analyses indicated that alcohol dependence genome-wide polygenic risk scores did not predict trajectory of alcohol use disorder symptoms, while family history of alcohol problems was associated with alcohol use disorder symptoms at the start of college but not with the rate of change in symptoms over time. Peer deviance and interpersonal traumatic events were associated with more alcohol use disorder symptoms across college years. Neither alcohol dependence genome-wide polygenic risk scores nor family history of alcohol problems moderated the effects of these environmental risk factors on alcohol use disorder symptoms. Our findings indicated that peer deviance and experience of interpersonal traumatic events are salient risk factors that elevate risk for alcohol problems among African American college students. Family history of alcohol problems could be a useful indicator of genetic risk for alcohol problems. Gene identification efforts with much larger samples of African descent are needed to better characterize genetic risk for alcohol use disorders, in order to better understand gene-environment interaction processes in this understudied population.

Polygenic Risk Score Prediction of Alcohol Dependence Symptoms Across Population-Based and Clinically Ascertained Samples.

Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples. Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N=4,304; FinnTwin12 [FT12], N=1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N=2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N=706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types. Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p<0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms. Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder.

Review: Genetic research on alcohol use outcomes in African American populations: A review of the literature, associated challenges, and implications.

There have been remarkable advances in understanding genetic influences on complex traits; however, individuals of African descent have been underrepresented in genetic research. We review the limitations of existing genetic research on alcohol phenotypes in African Americans (AA) including both twin and gene identification studies, possible reasons for underrepresentation of AAs in genetic research, the implications of the lack of racially diverse samples, and special considerations regarding conducting genetic research in AA populations. There is a marked absence of large-scale AA twin studies so little is known about the genetic epidemiology of alcohol use and problems among AAs. Individuals of African descent have also been underrepresented in gene identification efforts; however, there have been recent efforts to enhance representation. It remains unknown the extent to which genetic variants associated with alcohol use outcomes in individuals of European and African descent will be shared. Efforts to increase representation must be accompanied by careful attention to the ethical, legal, and social implications of genetic research. This is particularly true for AAs due to the history of abuse by the biomedical community and the persistent racial discrimination targeting this population. Lack of representation in genetic studies limits our understanding of the etiological factors that contribute to substance use and psychiatric outcomes in populations of African descent and has the potential to further perpetuate health disparities. Involving individuals of diverse ancestry in discussions about genetic research will be critical to ensure that all populations benefit equally from genetic advances. (Am J Addict 2017;26:486-493).

The Genetics of Addiction: Where Do We Go From Here?

We have made tremendous progress in understanding the genetic epidemiology of substance use problems. We understand a good deal about the genetic architecture of substance use disorders with respect to other psychiatric conditions, and how genetic influences change across development and as a function of the environment. We are further behind in identifying specific genes involved in substance use disorders. However, rather than blindly charging ahead with expensive gene identification efforts, our field would benefit from more thoughtful discussion about what strategies to pursue-both genetic and environmental-to have the greatest impact on reducing substance use problems.

Establishing a multidisciplinary context for modeling 3D facial shape from DNA.

Establishing a multidisciplinary context for modeling 3D facial shape from DNA.

Abstract 1298: Evidence for a genetic contribution to non-smoking-related lung cancer

Abstract Introduction: Familial clustering of lung cancer has long been noted; multiple genetic analyses of lung cancer pedigrees have been performed in search of lung cancer predisposition genes. Because smoking is also observed to cluster in families, this major environmental risk factor can confound any evidence for a genetic contribution to lung cancer. We show evidence that a genetic contribution appears likely to contribute to non-smoking-related lung cancer. Data and Methods: Using a population-based resource consisting of the computerized genealogy of the Utah pioneer founders and their descendants linked to a statewide cancer registry from 1966, we have analyzed the clustering of lung cancer cases among close and distant relatives. Using linked death certificate data that includes data on the contribution of tobacco to death, the subset of deceased lung cancer cases was stratified into smoking- (n=1895) and non-smoking-related (n=784) subsets. A test for a significant excess of pairwise relatedness among all cases was performed by comparing the average relatedness of these two independent subsets of lung cancer cases to the expected relatedness in the Utah population based on analysis of matched control sets (the well-published GIF method was used). Results: Significant evidence for overall excess pairwise relatedness was observed for the 784 lung cancer cases whose death certificate stated that tobacco did not contribute to death (p= 0.001). These results suggest familial clustering, but cannot discriminate between genetic- or environmental-based clustering. To remove any effect of a familial smoking effect that is not genetic, all pairwise relationships closer than third-degree were ignored; significant excess relatedness was still observed among non-smoking cases (p=0.019). When a similar analysis was performed for lung cancer cases whose death certificate indicated a contribution to death from tobacco (n=1895), overall significant excess relatedness was observed (p&amp;lt;0.001), suggesting familial clustering of cases; however, when close relationships were ignored there was no longer evidence for significant excess relatedness (p=0.271). Conclusions: Using published methods to analyze a powerful resource linking cancer data to genealogy we have shown that while lung cancers do appear to cluster in families, there are two distinct subsets of cases. The familial clustering of those cases who do not smoke provides strong evidence for a genetic contribution, while the familial clustering of those lung cancer cases who smoke appears to resemble the clustering expected with the shared environmental risk factor of smoking. Gene identification efforts should focus on the subset of lung cancer pedigrees representing cases for whom smoking did not contribute to lung cancer. Citation Format: Lisa A. Cannon-Albright, Shamus Carr, Wallace Akerley. Evidence for a genetic contribution to non-smoking-related lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1298. doi:10.1158/1538-7445.AM2014-1298

Measures of Current Alcohol Consumption and Problems: Two Independent Twin Studies Suggest a Complex Genetic Architecture

Twin studies demonstrate that measures of alcohol consumption (AC) show evidence of genetic influence, suggesting they may be useful in gene identification efforts. The extent to which these phenotypes will be informative in identifying susceptibility genes involved in alcohol dependence depends on the extent to which genetic influences are shared across measures of AC and alcohol problems. Previous studies have demonstrated that AC reported for the period of heaviest lifetime drinking shows a large degree of genetic overlap with alcohol dependence; however, many studies with genetic material assess current AC. Further, there are many different aspects of AC that can be assessed (e.g., frequency of use, quantity of use, and frequency of intoxication). Here, we use data from 2 large, independent, population-based twin samples, FinnTwin 16 and The Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, to examine the extent to which genetic influences are shared across many different measures of AC and alcohol problems. Genetic correlations across current AC measures and alcohol problems were high across both samples. However, both samples suggest a complex genetic architecture with many different genetic factors influencing various aspects of current AC and problems. These results suggest that careful attention must be paid to the phenotype in efforts to "replicate" genetic effects across samples or combine samples for meta-analyses of genetic effects influencing susceptibility to alcohol-related outcomes.

Using Dimensional Models of Externalizing Psychopathology to Aid in Gene Identification

Twin studies provide compelling evidence that alcohol and drug dependence, childhood conduct disorder, adult antisocial behavior, and disinhibitory personality traits share an underlying genetic liability that contributes to a spectrum of externalizing behaviors. However, this information has not been widely used in gene identification efforts, which have focused on specific disorders diagnosed using traditional psychiatric classification systems. To test the utility of using a multivariate externalizing phenotype in (1) linkage analyses and (2) association analyses to identify genes that contribute broadly to a spectrum of externalizing disorders. Data were analyzed from the Collaborative Study on the Genetics of Alcoholism. Linkage analyses were conducted using data from a genome-wide 10-cM microsatellite scan. Association analyses were conducted on 27 single-nucleotide polymorphisms genotyped across a candidate gene, the muscarinic acetylcholine receptor M2 gene (CHRM2). Six centers across the United States. Approximately 2300 individuals from 262 families. Lifetime symptom counts of alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder and novelty seeking, sensation seeking, and general externalizing component scores consisting of a composite of the previous 6 variables. Principal component analyses indicated that the 6 individual variables loaded on a single externalizing factor. Linkage analyses using the resultant component scores identified a region on chromosome 7 consistent with a gene that broadly predisposes individuals to externalizing behavior. Association analyses of a candidate gene, CHRM2, previously of interest in the Collaborative Study on the Genetics of Alcoholism, suggest that it is involved in a general externalizing phenotype. Broader conceptualizations of psychiatric disorders, such as studying a spectrum of externalizing psychopathology, may aid in identifying susceptibility genes and understanding the pathways through which genetic factors affect vulnerability for a variety of poor outcomes.

Cancer incidence in first-degree relatives of a population-based set of cases of early-onset breast cancer

Reliable determination of familial risks for cancer is important for clinical counselling, cancer prevention and understanding cancer aetiology. Family-based gene identification efforts may be targeted if the risks are well characterised and the mode of inheritance is identified. Early-onset breast cancer in a family member is a risk indicator for cancer among first-degree relatives; however, the familial risk pattern has not been assessed fully in population-based incidence studies. We estimated the risks for cancers of the breast, ovary and other sites among the first-degree relatives of 8868 patients in whom breast cancer was diagnosed before they reached the age of 50 years (diagnosed during the period 1943–1999). Population registers and parish records were used to identify 31,235 first-degree relatives, who were followed up to 31 December 2002 for occurrence of cancer by linkage to the Danish Cancer Registry. The observed incidence rates were compared with national rates adjusted for age, sex and calendar period. Overall, 39% of the 674 cases of breast cancer and 43% of the 143 cases of ovarian cancer among relatives were associated with a diagnosis of early-onset breast cancer in a family member. Among relatives under 50 years of age, the proportions were 56% and 58%, respectively, and among relatives 50 years or above the proportions were approximately 30% and 10%. In addition, a slightly but significantly increased risk for cancer of the cervix uteri was observed among relatives, and among those under 50 years of age, we found significantly increased risks for cancers of the colon and gall-bladder. In conclusion, the excess risk for breast cancer in first-degree relatives is large and remains sizable in the subgroup of female relatives aged 50 years or older, and that mutations in BRCA1/ 2 seem to explain only half of breast cancer cases attributable to family history.

Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism

The use of endophenotypes has been proposed as a strategy to aid gene identification efforts for complex phenotypes [Gottesman, I. I., and Shields J. (1972). Schizophrenia and Genetics: A Twin Study Vantage Point. London: Academic]. As part of the Collaborative Study of the Genetics of Alcoholism (COGA) project, we have analyzed electrophysiological endophenotypes, in addition to clinical diagnoses, as part of our effort to identify genes involved in the predisposition to alcohol dependence. In this paper we summarize published results from linkage and association analyses of two chromosomal regions in which the use of endophenotypes has successfully led to the identification of genes associated with alcohol dependence [GABRA2 (Edenberg et al., (2004). Am. J. Hum. Genet. 74:705-714) and CHRM2 (Wang et al., (2004). Hum. Mol. Genet. 13:1903-1911)]. Our experience in the COGA project has been that the analysis of endophenotypes provides several advantages over diagnostic phenotypes, including the strength and localization of the linkage signal. Our results provide an illustration of the successful use of endophenotypes to identify genes involved in the predisposition to a complex psychiatric phenotype, a strategy originally proposed by Gottesman and Shields in 1972.

Relationships between familial risks of cancer and the effects of heritable genes and their SNP variants

Familial risks for cancer can be used in many ways in guiding gene identification efforts and, more broadly, in understanding cancer etiology. Gene identification efforts may be properly designed and targeted if the familial risks are well characterized and the mode of inheritance is identified. Single nucleotide polymorphisms (SNPs) are extensively used in case–control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence, including differences in cancer incidence between regions and temporal changes within regions, indicates that cancer is mainly an environmental disease, with a minor heritable etiology. The large environmental component will hamper the success of SNP-based genetic association studies. Empirical familial risks should be used to evaluate the feasibility of such studies. We develop figures for the assessment of genetic parameters based on familial risks. Such data are helpful in the estimation of the expected genetic effects in cancer. Overall, we consider the likelihood of a successful application of SNPs in gene–environment studies small, unless established environmental risk factors are tested on proven candidate genes.