Segregation analysis of alcoholism in high density families: A replication

We have previously reported segregation analysis of alcoholism in 35 multigenerational families, each ascertained through a pair of male alcoholics by using the mixed model implemented by POINTER. This analysis suggested that liability to alcoholism was, in part, controlled by a major effect with or without additional multifactorial effects. The hypothesis that the major effect was explained by a single genetic locus with strictly mendelian transmission was rejected. The purpose of the present analysis was to use the regressive model implemented by the REGD program from the Statistical Analysis for Genetic Epidemiology computer package (S.A.G.E.) to confirm by replication that a major effect was present in these 35 families. Evidence for the major effect found in Pointer was replicated in the present analysis by using S.A.G.E. Also, we found strong evidence for parental effects that were independent of the major locus transmission from ancestral relatives to children. Mendelian transmission of this major effect was rejected when models incorporated parental effects. When the major effect was calculated adjusting for parental phenotypes, the relative risk of affection for children was about twice as high with affected parents vs. unaffected parents. © 1996 Wiley-Liss, Inc.     

Interactions between the <Emphasis Type="Italic">adducin 2</Emphasis>gene and antihypertensive drug therapies in determining blood pressure in people with hypertension

Background  

As part of the NHLBI Family Blood Pressure Program, the Genetic Epidemiology Network of Arteriopathy (GENOA) recruited 575 sibships (n = 1583 individuals) from Rochester, MN who had at least two hypertensive siblings diagnosed before age 60. Linkage analysis identified a region on chromosome 2 that was investigated using 70 single nucleotide polymorphisms (SNPs) typed in 7 positional candidate genes, including adducin 2 (ADD2).     

Strengthening the reporting of genetic risk prediction studies: the GRIPS statement

The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but the quality and completeness of reporting varies. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies, building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct, or analysis. A detailed Explanation and Elaboration document is published on the EJHG website.     

Reviews

Book reviewed in this article:
Population and Biological Aspects of Human Mutation.
Outline of Genetic Epidemiology.
Molecular Cloning. A Laboratory Manual.
Huntington's Chorea.
The Genetics of Neurological Disorders.     

Strengthening the reporting of genetic risk prediction studies (GRIPS): explanation and elaboration

The rapid and continuing progress in gene discovery for complex diseases is fueling interest in the potential application of genetic risk models for clinical and public health practice. The number of studies assessing the predictive ability is steadily increasing, but they vary widely in completeness of reporting and apparent quality. Transparent reporting of the strengths and weaknesses of these studies is important to facilitate the accumulation of evidence on genetic risk prediction. A multidisciplinary workshop sponsored by the Human Genome Epidemiology Network developed a checklist of 25 items recommended for strengthening the reporting of Genetic RIsk Prediction Studies (GRIPS), building on the principles established by previous reporting guidelines. These recommendations aim to enhance the transparency, quality and completeness of study reporting, and thereby to improve the synthesis and application of information from multiple studies that might differ in design, conduct or analysis.     

Kennedy病两个家系的临床表型、基因型和遗传特征分析

目的 分析两个Kennedy病家系的临床表型、基因型和家系特征.方法 收集Kennedy病患者的临床资料,用基因分析的方法 ,明确患者及家族成员雄激素受体基因第1外显子CAG序列的重复数.结果 A家系4代共58人,先证者39岁隐袭起病.B家系5代共61人,有两例患者分别于39岁、41岁缓慢起病.3例患者均以下运动神经元损害为特征,都出现了雄激素不敏感综合征的相关表现.血清肌酶呈轻中度升高;肌电图呈广泛前角损害;肌肉活检示神经源性肌萎缩;雄激素受体基因第1外显子中CAG重复数分别为49、48、47.两个家系的遗传方式均为X连锁隐性遗传.结论 Kennedy病多为中年男性隐袭起病,主要表现为延髓肌和脊髓肌的萎缩和无力,基因分析有助于对本病的确诊,并可明确携带者,以进行遗传咨询及产前诊断.     

Alzheimer disease is substantially preventable in the United States -- review of risk factors, therapy, and the prospects for an expert software system

Epidemiology studies, including both regional incidence and the analysis of specific risk factors for Alzheimer's disease indicate that substantial prevention of the disease, in the 50-70 percent range, is a practical possibility for the United States. Epidemiology has identified a rich diversity of specific prevention strategies relating to nutrition, dietary supplements, lifestyle, food and environmental toxins, and in some cases medication, many of which have a capacity to reduce Alzheimer's risk by 50 percent or more. The interaction of these risk factors with brain biology is increasingly understood. In contrast, therapeutic strategies for un-prevented Alzheimer's generally prove incapable of delaying disease progression by more than 3-11 months, because extensive brain cell death occurs even in preclinical or mild cases. A public health program aimed at prevention can be fashioned with expert software packages, based on already identified risk factors. Such statistical analysis should allow the prediction of individual and group Alzheimer's risks of sufficient power to instruct the formulation of lifestyle, nutritional and environmental programs to substantially reduce disease incidence. A less satisfactory but complementary alternative is very early disease detection with therapeutic strategies focused on retardation of brain cell death, so that the person dies of another cause before the disease is clinically manifested.     

Kennedy病两个家系的临床表型、基因型和遗传特征分析

目的 分析两个Kennedy病家系的临床表型、基因型和家系特征.方法 收集Kennedy病患者的临床资料,用基因分析的方法 ,明确患者及家族成员雄激素受体基因第1外显子CAG序列的重复数.结果 A家系4代共58人,先证者39岁隐袭起病.B家系5代共61人,有两例患者分别于39岁、41岁缓慢起病.3例患者均以下运动神经元损害为特征,都出现了雄激素不敏感综合征的相关表现.血清肌酶呈轻中度升高;肌电图呈广泛前角损害;肌肉活检示神经源性肌萎缩;雄激素受体基因第1外显子中CAG重复数分别为49、48、47.两个家系的遗传方式均为X连锁隐性遗传.结论 Kennedy病多为中年男性隐袭起病,主要表现为延髓肌和脊髓肌的萎缩和无力,基因分析有助于对本病的确诊,并可明确携带者,以进行遗传咨询及产前诊断.     

Kennedy病两个家系的临床表型、基因型和遗传特征分析

目的 分析两个Kennedy病家系的临床表型、基因型和家系特征.方法 收集Kennedy病患者的临床资料,用基因分析的方法 ,明确患者及家族成员雄激素受体基因第1外显子CAG序列的重复数.结果 A家系4代共58人,先证者39岁隐袭起病.B家系5代共61人,有两例患者分别于39岁、41岁缓慢起病.3例患者均以下运动神经元损害为特征,都出现了雄激素不敏感综合征的相关表现.血清肌酶呈轻中度升高;肌电图呈广泛前角损害;肌肉活检示神经源性肌萎缩;雄激素受体基因第1外显子中CAG重复数分别为49、48、47.两个家系的遗传方式均为X连锁隐性遗传.结论 Kennedy病多为中年男性隐袭起病,主要表现为延髓肌和脊髓肌的萎缩和无力,基因分析有助于对本病的确诊,并可明确携带者,以进行遗传咨询及产前诊断.     

α1 Antitrypsin deficiency and liver disease in childhood: genetic, immunochemical, histological, and ultrastructural diagnosis

alpha(1) Antitrypsin deficiency is a significant factor in the pathogenesis of neonatal cholestasis and progressive juvenile cirrhosis. The diagnosis may be suggested by the liver biopsy appearances and confirmed by immunochemical analysis of the serum. Genetic counselling of affected families is of importance, as medical treatment is ineffective at the present time.     

Reviews

Book reviewed in this article:
Genetic Epidemiology . Edited by N ewton E. M orton and C hin S ik C hung
Evolutionary Biology . Volume 11. Edited by M. K. H echt , W. C. S teere and B. W allace
Clinical Atlas of Human Chromosomes . By J ean D e G rouchy and C atherine T urleau
Myotonic Dystrophy . By P. S. H arper . Eastbourne: W. B. Saunders.     

Parent-of-origin effect in the segregation analysis of bipolar affective disorder families

OBJECTIVE: The purpose of this study is to test for heterogeneity in bipolar families based on the differential parental transmission of disease. METHODS: Complex segregation analyses of 260 bipolar families, ascertained by the Johns Hopkins Bipolar Disorder Study, was performed based on the evidence for a parent-of-origin effect in the inheritance pattern by using REGD in Statistical Analysis for Genetic Epidemiology, Release 3.1 program. RESULTS: A Mendelian dominant model provided the best explanation in 57 paternal pedigrees (pedigrees with an affected paternal lineage). No evidence of Mendelian inheritance existed among 141 pedigrees showing maternal transmission. A likelihood ratio test for heterogeneity on the basis of best-fitting Mendelian dominant model showed significant differences between these two groups. CONCLUSION: These results suggest that pedigrees with no evidence of maternal transmission of bipolar disorder may represent a unique genetic subgroup of multiplex bipolar families.     

Retrospective access to data: the ENGAGE consent experience

The rapid emergence of large-scale genetic databases raises issues at the nexus of medical law and ethics, as well as the need, at both national and international levels, for an appropriate and effective framework for their governance. This is even more so for retrospective access to data for secondary uses, wherein the original consent did not foresee such use. The first part of this paper provides a brief historical overview of the ethical and legal frameworks governing consent issues in biobanking generally, before turning to the secondary use of retrospective data in epidemiological biobanks. Such use raises particularly complex issues when (1) the original consent provided is restricted; (2) the minor research subject reaches legal age; (3) the research subject dies; or (4) samples and data were obtained during medical care. Our analysis demonstrates the inconclusive, and even contradictory, nature of guidelines and confirms the current lack of compatible regulations. The second part of this paper uses the European Network for Genetic and Genomic Epidemiology (ENGAGE Consortium) as a case study to illustrate the challenges of research using previously collected data sets in Europe. Our study of 52 ENGAGE consent forms and information documents shows that a broad range of mechanisms were developed to enable secondary use of the data that are part of the ENGAGE Consortium.     

Semi-parametric empirical Bayes factor for genome-wide association studies

Bayes factor analysis has the attractive property of accommodating the risks of both false negatives and false positives when identifying susceptibility gene variants in genome-wide association studies (GWASs). For a particular SNP, the critical aspect of this analysis is that it incorporates the probability of obtaining the observed value of a statistic on disease association under the alternative hypotheses of non-null association. An approximate Bayes factor (ABF) was proposed by Wakefield (Genetic Epidemiology 2009;33:79–86) based on a normal prior for the underlying effect-size distribution. However, misspecification of the prior can lead to failure in incorporating the probability under the alternative hypothesis. In this paper, we propose a semi-parametric, empirical Bayes factor (SP-EBF) based on a nonparametric effect-size distribution estimated from the data. Analysis of several GWAS datasets revealed the presence of substantial numbers of SNPs with small effect sizes, and the SP-EBF attributed much greater significance to such SNPs than the ABF. Overall, the SP-EBF incorporates an effect-size distribution that is estimated from the data, and it has the potential to improve the accuracy of Bayes factor analysis in GWASs.Subject terms: Epidemiology, Genetics     

Genetic polymorphisms in fatty acid metabolism genes and colorectal cancer

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included dietary fat intake; consequently, the role of genes in the fatty acid biosynthesis and metabolism pathways is of particular interest. Moreover, hyperlipidaemia has been associated with different type of cancer and serum lipid levels could be affected by genetic factors, including polymorphisms in the lipid metabolism pathway. The aim of this study is to assess the association between single-nucleotide polymorphisms (SNPs) in fatty acid metabolism genes, serum lipid levels, body mass index (BMI) and dietary fat intake and CRC risk; 30 SNPs from 8 candidate genes included in fatty acid biosynthesis and metabolism pathways were genotyped in 1780 CRC cases and 1864 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. Several LIPC (lipase, hepatic) polymorphisms were found to be associated with CRC risk, although no particular haplotype was related to CRC. The SNP rs12299484 showed an association with CRC risk after Bonferroni correction. We replicate the association between the T allele of the LIPC SNP rs1800588 and higher serum high-density lipoprotein levels. Weak associations between selected polymorphism in the LIPC and PPARG genes and BMI were observed. A path analysis based on structural equation modelling showed a direct effect of LIPC gene polymorphisms on colorectal carcinogenesis as well as an indirect effect mediated through serum lipid levels. Genetic polymorphisms in the hepatic lipase gene have a potential role in colorectal carcinogenesis, perhaps though the regulation of serum lipid levels.     

Linkage relationships between a major gene for catechol-o-methyltransferase activity and 25 polymorphic marker systems

Segregation analysis has provided evidence suggesting the existence of a major gene for catechol-o-methyltransferase (COMT) activity in man. Five large families (4 Caucasian, 1 black), with a total of 1,189 individuals, were ascertained as part of a genetic study of blood pressure. Erythrocyte COMT activity and status at 25 polymorphic genetic marker loci were determined on more than 518 individuals in these pedigrees. Genetic linkage analysis of COMT with each of the 25 marker loci was performed in two ways: (1) using parameter estimates from segregation analysis of untransformed COMT activity, and (2) using parameter estimates from segregation analysis of the power transformation of the COMT activity that maximized the likelihood of the genetic hypothesis in each family. Tight and close linkage were excluded at 21 and 15 loci, respectively. A lod score of 1.27 at θ = 0.1 was found between the loci for COMT activity and phosphogluconate dehydrogenase (PGD). Transformation of the data had little effect on the outcome of the linkage analysis.     

Reviews

Book reviewed in this article: Comparative Mammalian Cytogenetics. Edited by Kurt Benirschke Epidemiology of Mongolism. By A. M. Lilienfeld and C. H. Benesch A Study of the early Development of Mongols. By Valerie A. Cowie Medizinische Genetik Grundlagen, Ergebnisse und Problems. By Widukind Lenz Classification and Biology. By E,. A. Crowson An ABC of Medical Genetics. By C. O. Carter Equilibrium Behaviour of Population Genetic Models with Non-Random Mating. By Samuel Karlin The Biology of Twinning in Man. By M. G. Bulmer An Introduction to Probability Theory. By P. A. P. Moran Computer Applications in Genetics. Edited by Newton E. Morton A Genetics Program Library. Edited by Newton E. Morton