Evidence For Familial Aggregation Research Articles

Familial aggregation of atopic dermatitis and co-aggregation of allergic diseases in affected families in Taiwan

BackgroundAtopic dermatitis (AD) is contributed from a result of genetic and environmental interaction. The evidence for familial aggregation in AD has been reported but population-based studies and co-aggregation with other allergic diseases are rarely reported. ObjectiveThis study examined familial aggregation and heritability of atopic dermatitis (AD) and to estimate the relative risks (RRs) of other allergic diseases in individuals with relatives diagnosed with AD. MethodsWe used Taiwan National Health Insurance Research Database to identify all registered beneficiaries (n = 26,525,074) in 2015; among them, 1,248,594 individuals had AD. We estimated familial risks of AD and other allergic diseases by using marginal Cox proportional models. ResultsPrevalence of AD in individuals with relatives affected with atopic dermatitis was 3.1-fold higher than the general population (12.4 % vs. 4.0 %, respectively). The adjusted relative risks (RR) for individuals with an affected first-degree relative (FDR) was 2.25 (95 % CI, 2.25–2.26). The adjusted RRs for subjects with an affected parent, an affected offspring or an affected sibling was 2.39 (95 % CI, 2.37–2.41), 2.26 (95 % CI, 2.24–2.28) and 2.30 (95 % CI, 2.29–2.31) respectively. The RRs in individuals with an FDR with AD was 1.34 (95 %CI, 1.34 – 1.34) for asthma and 1.23 (95 %CI, 1.23–1.24) for allergic rhinitis. ConclusionThis nationwide study ascertains that a family history of atopic dermatitis is a risk factor for atopic dermatitis. Individuals with relatives affected by atopic dermatitis have slightly higher risks of developing asthma and allergic rhinitis.

Familial Aggregation of Psoriasis and Co-Aggregation of Autoimmune Diseases in Affected Families.

Psoriasis is considered to result from the interaction of genetic factors and environmental exposure. The evidence for familial aggregation in psoriasis has been reported but population-based studies related to the magnitude of genetic contribution to psoriasis are rare. This study aimed to evaluate the relative risks of psoriasis in individuals with affected relatives and to calculate the proportion of genetic, shared, and non-shared environmental factors contributing to psoriasis. The study cohort included 69,828 patients diagnosed with psoriasis enrolled in National health Insurance in 2010. The adjusted relative risks (RR) for individuals with an affected first-degree relative and affected second-degree relative were 5.50 (95% CI (Confidence Interval), 5.19–5.82) and 2.54 (95% CI, 2.08–3.12) respectively. For those who have affected first-degree relatives, their RR was 1.45 (95% CI, 1.17–1.79) for Sjogren’s syndrome and 1.94 (95% CI, 1.15–3.27) for systemic sclerosis. This nationwide study ascertains that family history of psoriasis is a risk factor for psoriasis. Individuals with relatives affected by psoriasis have higher risks of developing some autoimmune diseases.

Evidence for familial aggregation in siblings with autoimmune rheumatic diseases

Evidence for familial aggregation in siblings with autoimmune rheumatic diseases

Lack of familial aggregation in chronic constipation excluding irritable bowel syndrome: a population-based study.

Despite strong evidence supporting a genetic and gene-environment interaction in the irritable bowel syndrome (IBS), the role of genes and early life in another common functional bowel disorder, chronic constipation (CC), have been little studied. To determine whether familial aggregation occurs in CC and whether risk factors differed in those with family members. A randomly selected population-based cohort from Olmsted County, MN, was surveyed (n = 8,006); 3,831 completed questionnaires (response rate 48 %). Cases were identified based upon their responses to a validated questionnaire and meeting Rome criteria for CC. Controls were matched one to one by age and gender. IBS (by Rome II criteria) was excluded. Recruitment of case and control probands occurred in 2010-2011 by mailing a family information form; then, first-degree relatives (FDR) were mailed a questionnaire. All potential proband participants were not informed of CC status. Overall 1,185 cases who met criteria for CC without symptoms of IBS and 1,185 controls were surveyed; 309 case and 336 control probands provided data. The proportion of family members having CC was not associated with case status, and the constipation status of FDR was not significantly associated with case-controls status of the respective probands. Symptom burden in FDR was associated with gender and SSC score, but not age or proband status. No evidence of familial aggregation was observed in adults from the community with CC (excluding IBS). Our data suggest environmental factors in later life more likely account for adult CC.

Abstract 36: Changes in HDL Particle Traits in Response to Regular Exercise: Results from the HERITAGE Family Study

Given the controversy around HDL-C as a therapeutic target, there is a need to investigate other features of HDL and how they respond to various preventive interventions. We tested the hypothesis that regular exercise would have beneficial effects on HDL particle (HDL-P) traits in sedentary adults. Methods: The following HDL-P traits were measured via NMR (Liposcience Inc.) before and after completion of a 20-week exercise program in the HERITAGE Family Study (N=715): concentration of total, large, medium, and small HDL-P and mean HDL-P size. ANCOVA was used to test for aggregation of HDL-P trait responses in families controlling for age, sex, and baseline BMI and trait value. Results: The concentration of large HDL-P significantly increased in response to regular exercise in both Black and White participants, while the increase was significantly larger in females compared to males (Table 1). In general, regular exercise decreased the concentration of medium and small HDL-P. Together, these responses contributed to a significant increase in the average cholesterol content of HDL particles. Exercise-induced changes in large HDL-P were inversely correlated with changes in fat mass and systolic blood pressure. Moreover, changes in BMI were significantly associated with changes in all of the HDL-P traits, but not with HDL-C. We found significant evidence of familial aggregation for the exercise-induced changes in HDL-P traits in both races, as there was 1.4 to 1.6 times more variance between than within families for the changes in total (p=0.02 in Whites) and large HDL-P (p=0.004 in Whites, p=0.02 in Blacks) and HDL-P size (p=0.0009 in Whites, p=0.009 in Blacks). Conclusion: The HDL-P subclass profile favorably responded to regular exercise in sedentary Black and White adults, highlighted by increases in the concentration of large HDL-P, and may be influenced by a significant genetic component. We provide evidence that regular exercise could potentially be used as an HDL-based therapy designed to target beneficial subfractions.

Consideration for gene-environment interactions as novel determinants of exfoliation syndrome.

In systemic biology one uses high throughput data from various study types to derive information on better ways to diagnose, treat, and prevent complex diseases like exfoliation syndrome (XFS) (Figure). Here we focus on how analytical epidemiological studies contribute to an improved understanding of XFS and its attendant unwanted consequences (such as glaucoma,1 cataract,2 retinal vein occlusion,3 etc.). Specifically, we concentrate on how the environment may modify the association between genotypes and exfoliation syndrome (XFS). The discovery of gene-environment (GxE) interactions for XFS may form the basis for novel XFS primary prevention strategies. It should be stated at the outset that GxE interactions for XFS have not been confirmed but several are suspected. The discovery of the robust association between LOXL1 genotypes and XFS4 has led directly to the discovery of environmental risk factors or the disease, setting the stage to assess GxE interactions for this condition. This review will cover how the association between LOXL1 genotypes and XFS was discovered and confirmed. The impact of the geographical distribution of LOXL1 gene variants on the identification of environmental risk factors will be reviewed. The strongest candidate GxE interactions for XFS will be presented, and the implications these have for understanding the disease and for targeted strategies to reduce disease burden will be described. Finally, the necessary steps required for testing putative interactions between LOXL1 gene variants and environmental factors will be discussed. Figure A systems biology approach is required to assimilate how genes and environment contribute to the formation of exfoliation material in the human eye as illustrated in the clinical photograph with the white arrow that points to a sheet of exfoliation material ... The discovery of LOXL1 variants in relation to exfoliation syndrome XFS is a strongly age-related disease,5 making it difficult to collect multigenerational families with the disorder, although some evidence of familial aggregation has been reported.6 Using a large Finnish family for genome wide linkage study, several genomic regions were suggested to contain genes contributing to XFS.7 However, further study has not identified disease-associated genes in these regions, suggesting loci in these regions are not common causes of XFS. Candidate gene studies using selected genes of interest in case control studies of unrelated individuals have been performed. However, these studies have been mostly underpowered and the results have been inconsistently replicated across populations.8 The results from Phase I of The Human Genome Project suggested that an agnostic search for gene variants related to any trait is possible.9 First, the human genome contains DNA blocks that tend to travel together during cell reproduction. The size of such blocks differs by ancestry. Second, roughly every 300th base, there is a nucleotide change that occurs commonly (>5% of the time) in the general population, referred to as a common single nucleotide polymorphism (SNP). These realizations combined with improvements in microfabrication and nucleotide chemistry assays allowed for the creation of technologies that can simultaneously genotype several hundred thousand common polymorphic sites strategically located throughout the genome. Thus, these genotyping technologies enabled genome wide association studies (GWAS), which are agnostic searches for common polymorphisms that have associations with complex diseases, like XFS. An adequately powered GWAS using a case control design performed in Iceland demonstrated that LOXL1 variants were associated with XFS.4 The researchers used a simple chi square test to compare the genotype frequency between cases and controls at 304,250 loci throughout the genome. The association between each marker in cases and control was adjusted for inherent population structure that might confound the relation between a genotype and affected status. The typical p-value for statistical significance (p=0.05) was adjusted to 1.6 × 10−7 using the Bonferroni method by dividing 0.05 by the number of tests performed (304,250). Using this approach, polymorphic variants located in the genomic region that includes LOXL1 were found to be statistically associated with XFS. These results were confirmed using a candidate approach in another population of subjects as part of the same publication. There were two rather remarkable features of the XFS GWAS performed by the Icelandic group. First, the effect size for the rs3825942 LOXL1 variant found in association with XFS was among the highest seen in a GWAS for common complex disease (odds ratio = 20.1); typically, odds ratios for SNPs in association with common complex diseases are in the 1.2-1.5 range and rarely are they above 2.0. This suggests that the rs3825942 allelic variant represents a locus of major functional significance in XFS. Second, while 99% of cases harbored the at-risk allele, 85% of controls also harbored this allele. This suggests that while the rs3825942 LOXL1 variant is necessary for disease, it was not sufficient to produce it. Additional factors that could produce XFS include other genes, environmental factors or epigenetic factors.

Familial risk in pediatric cancer and implications for practice.

9561 Background: Using a unique genealogical resource, the Utah Population Database, we examined risk of cancer in 1st- through 3rd-degree relatives of 4,482 pediatric cancer cases ≤18 years old diagnosed between 1966 and 2009. We quantified cancer risk in relatives of children with cancer in order to determine evidence of a familial aggregation of cancer, identify high-risk pedigrees, and inform counseling protocols for genetic testing and screening. Methods: We estimated cancer risk in relatives of pediatric cases compared to random population controls matched 5:1 on sex, birth year, and birthplace. Odds ratios were calculated using conditional logistic regression, adjusting for number of biological relatives, their degree of relatedness, and their person-years at risk. We included all relatives of cases and controls with followup who linked to a pedigree of ≥2 generations; this approach has been shown to lead to unbiased risk estimates. As observations within families are non-independent, a robust variance estimator for cluster-correlated data was incorporated. Results: Mostly siblings, 1st-degree relatives (N=49 affected) of pediatric cases were at 2-fold increased risk of being diagnosed at age<19 with cancer themselves (p<10-4); siblings of cases diagnosed at age<5 had a 4-fold risk of pediatric cancer (p<10-7). Likewise, 2nd-degree relatives (N=61 affected) and cousins (N=105 affected) of cases had a ~2-fold risk of childhood cancer (p<10-4). Proband siblings were at increased risk for leukemia, brain tumor, epithelial neoplasia, and bone cancer. While 1st-degree relatives of pediatric cases had a slight increased risk of adult-onset cancer, when they do develop cancer they exhibit a 50% increased risk of a Li-Fraumeni Syndrome-related tumor diagnosis (N=142 affected relatives; p<10-4). Conclusions: Our findings provide evidence of familial aggregation of cancer and suggest a higher percent of pediatric cancers are related to hereditary syndromes than are adult cancers. We encourage a 3-generation family history be collected and routinely updated for all pediatric cancer patients, and those children with family histories of early-onset cancer be referred for genetic counseling and early surveillance when appropriate.

AS36-02 - Chronic course of depression in the general population

Introduction The prevalence and course of chronic major depressive disorders (MDD) in the general population has rarely been assessed. Objectives to gain a better understanding of the prevalence, course and the familial aggregation of MDD with at least one episode exceeding a duration of two years. Aims to assess 1) the prevalence; 2) course characteristics and comorbidity with other psychiatric disorders and 3) cardiovascular risk factors (CVRFs) and 4) the familial aggregation of chronic MDD in subjects with chronic MDD. Methods The sample stems from a large community survey carried out in the city of Lausanne, Switzerland. Subjects were aged from 35 to 65 years (n = 3717, 53.1% females, mean age: 50.9 years). They all underwent a physical examination of CVRFs and a psychiatric evaluation using the semi-structured Diagnostic Interview for Genetic Studies. Results 1) Approximately 15% of the sample reported at least one chronic depressive episode and 6% were in a chronic depressive episode at the time of the interview; about a 6 th of them had episodes longer than 10 years; 2) compared to non-chronic MDD, MDD with chronic depressive episodes was associated with low socio-demographic level, comorbidity with anxiety disorders and almost all variables indicating poor course, but not with CVRFs except for inactivity; 4)there was no evidence for familial aggregation of chronic MDD. Conclusions As expected, MDD with chronic episodes revealed a strong association to indicators of poor course. However, with the exception of inactivity they do not seem to be associated with CVRF.

Abstract A62: Tobacco exposure, risk for bladder cancer, and modification by NAT2 in different ethnic populations

Abstract Introduction: Occupational exposure to arylamine compounds is a well-established risk factor for bladder cancer. With greater regulation, industrial arylamine exposure in the United States has reduced, thus making tobacco smoke the predominant source of arylamine exposure. Though exposure is greater in China than in the US, bladder cancer rates are higher in the US. These circumstances, together with evidence of familial aggregation of bladder cancer, have long suggested a role of inherited genetic factors in disease etiology. Previous studies indicate that slow variants of polymorphic N-acetyltranseferase, an arylamine-metabolizing enzyme encoded by the NAT2 locus, is a risk factor. Differences in distribution of slow acetylation may underlie demonstrated ethnic differences in bladder cancer risk. Thus cases of transitional cell carcinoma of the urinary bladder were studied to understand the role of the NAT2 gene and arylamine exposure differences between Caucasians and Chinese. Methods: A population-based case-control study of bladder cancer conducted in Los Angeles County (LA), California and Shanghai, China. Cases were diagnosed with urothelial carcinoma from 1987 to 1996 and from 1995 to 1998 in Shanghai. Controls were matched on gender, age in both populations, with further matching on neighborhood in Los Angeles. Participants completed in-person interviews providing information on several risk factors including smoking. All Shanghai participants and those LA participants interviewed from 1992 onward provided peripheral blood samples. Participants also provided samples of urine following timed ingestion of caffeine from which urinary metabolite ratios were assessed as a phenotypic measure of NAT2 activity. Genotypic analysis of 30 Tag SNPs within the NAT2 locus was conducted, and inferred phenotype assigned by haplotype analysis (SAS/Genetics, Proc Haplotype) followed by assignment of “slow” and “rapid” alleles according to consensus NAT2 gene nomenclature (http://louisville.edu/medschool/pharmacology/consensus-human-arylamine-n-acetyltransferase-gene-nomenclature/nat_pdf_files/Human_NAT2_alleles.pdf) was done. Gene-disease associations were estimated in subsequent statistical analysis employing logistic regression using N:M matching and an additive model for genetic effect. Results: 786 (LA) and 1026 (Shanghai) participants contributed to the analysis. As previously reported (Carcinogenesis 29:1386, 2008), bladder cancer risk was associated with “slow” measured phenotype among the LA participants who reported smoking 30 or more pack-years. Among LA participants, we further observed that rs1495741A (OR=1.47, 95% CI: 1.08–1.99) to be associated with risk, as reported for a separate study population of European origin (Pharmacogenetics and Genomics 21:231,2011). Among Shanghai participants, “slow” measured phenotype was also associated with risk (OR=1.44, 95% CI: 1.08–1.92). Unexpectedly, among Shanghai participants, both the “slow” inferred phenotype and rs1495741A allele were associated with risk in the direction opposite to that observed among LA participants (OR=0.65, 95% CI: 0.44–0.94; OR=0.70, 95% CI: 0.50–0.97). Based upon consensus NAT2 gene nomenclature, nearly 29% of Shanghai participants had at least one haplotype defined as a “slow substrate dependent” allele, whereas such alleles were observed in fewer than 3% of LA participants. Conclusions: Lower bladder cancer occurrence among Chinese compared with non-Hispanic whites may be related in part to differences in genetic susceptibility. Additional studies are ongoing to clarify whether ethnic differences in associations to inferred phenotype and to rs1495741A arise from differences in organization of the NAT2 locus between populations of European and Chinese descent as well as differential exposure of these populations to mono-versus diarylamines (Int J Cancer 118:161, 2006), or perhaps to both of these factors. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A62.

Epidemiología genética de la artritis reumatoide: ¿qué esperar de América Latina?

Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammation and destruction of the synovial joints. It affects approximately 0.5% of the Latin-American population and is three times more common in women than in men. Evidence of familial aggregation (lambdas=2-17) was the first indication of a genetic susceptibility to disease. As in other autoimmune diseases, it has a complex genetic basis. Results from whole-genome scans indicate that the HLA region contains a significant and consistent set of linked loci. However, HLA accounts for only one-third of the genetic susceptibility of disease, indicating that non-HLA genes are also involved in the disease susceptibility. In Latin-America, association with HLA-DRB1*0404 and TNF -308A alleles has been uniformly established; however, many other candidate genes remain to be studied. The identification of genetic factors conferring susceptibility to rheumatoid arthritis will contribute to the knowledge of the pathogenic mechanisms, ability to predict its occurrence, the development of diagnostic tools, prognosis, and treatment. The genetic epidemiology of rheumatoid arthritis is herein reviewed; a set of recommendations is provided for the design, analysis and interpretation of genetic association studies in the context of Latin-American populations.

Abstract 2128: Whole transcriptome sequencing in normal and cancer prostate tissue

Abstract Prostate cancer (PrCa) is the second most common type of cancer in males. Established risk factors for PrCa are age, ethnicity and family history. PrCa shows consistent evidence of familial aggregation and heritable factors have been estimated to explain 42% (29-50%) of disease risk in individuals of European ancestry. More than 20 regions harboring genetic risk variants associated with increased risk of PrCa have been identified through Genome-wide association studies (GWAS) to date (MSMB, HNF1B, SLC22A3, LMTK2, KLK2-KLK3, NUDT11, THADA, ITGA6, PDLIM5, TET2, NKX3.1, TH, TTLL1, EHBP1, CTBP2, JAZF1 and 3p12.1, 7p15.3, 8q24, 11q13.3 and 12q13.13 genomic regions). We began to investigate and characterize the entire transcriptome of normal and cancer prostate tissue through a massively parallel sequencing technology (Illumina /Solexa Genome Analyze II). We generated transcriptome profiles based on 36 or 72 bp paired-end reads for cell lines established from cancer and matching normal tissue from two patients. To analyze the data, we used BWA, Bowtie, Tophat packages and Partek Genomics Suite software. More than 80% of the sequence reads were mapped to the human reference sequence (hg19). The aligned sequences were examined for presence of alternative splicing forms, novel exons, non-coding transcripts and chimeric events compared with a reference transcript annotation from RefSeq Genes of UCSC genome browser database. Based on RPKM algorithm, we also evaluated the expression level in the cancer and normal tissues. We detected over 70,000 transcripts and of ∼ 5, 000 of them were novel splicing isoforms not present in the UCSC database. We examined transcriptome landscape in GWAS-identified loci associated with PrCa. Within the 8q24 region we observed differential expression or evidence of alternative transcripts for SRRM1L, POU5F1B and LOC72767. Within 11q13.3 we observed a novel transcript found only in normal prostate tissue. Many of the risk candidate genes such as ITGA6, PDLIM5, THADA, TET2, SLC22A3, CTBP2 and EHBP1 had multiple splicing isoforms and some of these isoforms were differentially expressed between normal and tumor samples. The expression of alternative transcripts will be confirmed by qPCR in independent samples and correlated with cancer -associated genetic variants identified by GWAS. In conclusion, we generated a resource for studies of PrCa. This reference set will be useful for functional exploration of genetic association signals detected through GWAS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2128.

5. Genetics of allergic disease

Genetic variation provides the basis for differences in the host response to a variety of environmental factors that can result in complex genetic diseases, including asthma and atopy. Through our ability to capture genetic variation at the single-nucleotide level and our increasing ability to perform large-scale sequencing of the human genome, including the development of computer algorithms for improved data analysis, our understanding of these complex diseases has increased dramatically in recent years. The genetics of allergy have shifted from characterizing a single polymorphism in a candidate gene as being responsible for the disease to inclusion of a multitude of genetic and nongenetic risk factors. Studies now must consider complex relationships that modify an individual's susceptibility, including possible gene-environment and gene-gene interactions and possible epigenetic modification of the genome. This review will discuss the techniques used for genetic analysis of complex diseases, some of the important genes that have been replicated in multiple asthma studies, and the future of genetic studies in asthma.

Consortium approach to identifying genes for Barrett’s esophagus and esophageal adenocarcinoma

Consortium approaches are becoming increasingly more common for a variety of chronic diseases and conditions. The Familial Barrett's Esophagus Consortium began in 1998 and was originally designed to investigate the evidence for familial aggregation of Barrett's esophagus, esophageal adenocarcinoma, or esophagogastric junctional adenocarcinoma. The authors have shown that this phenotype does in fact aggregate in families; therefore, linkage analyses are currently underway. The Consortium, whose goals and membership are growing, has been successfully established and maintained. In this article, details about the research design and membership are provided, as are the current and future goals of the Consortium. The authors believe that this time is especially exciting for research in this area, and they look forward to answering more questions relevant to these diseases with regard to both genetic and environmental risk factors to ultimately design more effective treatment and prevention strategies.

Decomposing the autism phenotype into familial dimensions

The objective of this article is to decompose the level of functioning phenotype in autism to see if it can be conceptualized as two simpler, but still familial, dimensional phenotypes of language and non-verbal IQ. We assembled 80 sibpairs with either autism, Asperger syndrome or atypical autism. To see whether the familial correlation on language scores was accounted for by the familial correlation on non-verbal IQ, residual language scores were calculated for each member of the sibpair based on a multiple regression equation using their IQ score as an explanatory or independent variable and controlling for the age and gender of the affected individual. These residual scores were then used to calculate intraclass correlations between affected sibs. This process was repeated using IQ as the dependent variable and language as a covariate. Within affected individuals there was a strong relation between non-verbal IQ (as measured by the Leiter performance scale) and language (as measured by the Vineland Communication Scale). In addition, there was familial correlation between sibs on both measures. Evidence of familial aggregation on both non-verbal IQ and language remained even after partialling out the effect of the covariates by regression analysis and by generalized estimating equation. These findings suggest that non-verbal IQ and language in PDD may arise from independent genetic mechanisms. The implications of this finding for linkage analysis and for identifying genetically informative phenotypes are discussed.

Genetics of Food Intake and Eating Behavior Phenotypes in Humans

This review summarizes the research advances of the past decade regarding the role of human genetic differences in energy and nutrient intake as well as in eating behavior phenotypes and selected eating disorders. The evidence for familial aggregation and heritability based on twin and nuclear family study designs is summarized. Genome-wide linkage scans and quantitative trait loci identified to date are discussed. DNA sequence variants in candidate genes are reviewed. Single genes associated with classical eating disorders are also incorporated. Epigenetic events will need to be incorporated in future studies designed to investigate the effects of DNA variants on dietary phenotypes. Understanding the relative contribution of global genetic variation and of DNA sequence variants in specific genes is important in the effort to influence dietary habits in a healthier direction.

LRRK2G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews

To the Editor: Most cases of Parkinson's disease are considered sporadic and idiopathic, although there is evidence of familial aggregation, and several monogenic forms have been identified.1 Recen...

Genetic Influence on Dystocia

Dystocia, a prolonged and difficult labor, complicates from 3% to 8% of all deliveries worldwide. There is evidence of familial aggregation of the disorder, prompting this population-based retrospective study using registry information on dystocia in sisters and mothers. The goal was to detect any genetic influences on susceptibility to dystocia. The study group included 2,539,534 births taking place in Sweden from 1973 through 1997. Relationships between sibling and mother-daughter pairs were examined, and model fitting served to estimate the relative contributions of genetic and environmental factors to dystocia. The incidence of dystocia, identified in 190,747 births, was 8%. Compared with a monozygotic twin whose cotwin did not have dystocia, 1 whose cotwin did have dystocia exhibited a nearly 4-fold increase in the risk of dystocia. Considering all diagnoses of dystocia, the odds ratio was highest for monozygotic twins at 3.82. For dizygotic twins (biologically full-sisters), half-sisters with the same mother, and mother-daughter pairs, the respective odds ratio values were 1.66, 1.85, and 1.60. Half-sisters sharing the same father had a lower risk of dystocia. Model fitting suggested that genetic effects accounted for 28% of susceptibility to dystocia (95% confidence interval, 21-32%). Nonshared environmental factors accounted for 67% of susceptibility. The same patterns were found for primary and secondary dystocia. When analyzing women with primary dystocia who had cesarean section, the risk of dystocia was significantly elevated only in monozygotic twins and mother-daughter pairs. These findings suggest that detecting genes related to dystocia might clarify the pathophysiological of this disorder, and might make it possible to detect, before parturition, an increased risk of dystocia.

Molecular genetics of affective disorders

Evidence for familial aggregation in Affective Disorders (AD) has been provided in classical studies. Linkage and association genetic studies have been proposed to detect genetic factors implicated in AD. However, findings from molecular genetic studies remain inconclusive. Nevertheless, current research is focusing on the phenotypes, both sub- and endophenotypes. In addition, recent advances in technology, such as microarrays, provide new tools in psychiatric genetics. These different approaches offer a new optimism era in the search of genetic factors in AD.

The genetics of systemic lupus erythematosus: putting the pieces together.

With lambda(s) estimates of 10 to 20 and other evidence of familial aggregation, as well as a monozygotic twin concordance rate >20, systemic lupus erythematosus (SLE) would appear to be a very promising phenotype using modern genetic approaches. Indeed, genetic associations are already known at numerous candidate loci including various HLA alleles, complement component genes, Fcgamma receptors, and others, and murine genetic studies of lupus models have provided additional candidate genes and potential syntenic linkages to evaluate in man. The completed genetic linkage studies performed on various collections of pedigrees multiplex for SLE have identified 60 susceptibility loci with varying degrees of evidence for linkage in man. Seven of these meet or exceed the threshold for significant linkage (LOD > or = 3.3 or P < or = 0.00005) at 1q22-23, 1q41, 2q37, 4p16, 6p21-11, 16q13 and 17p13. In addition, these linkages usually dominate in one ethnicity or another, suggesting that the responsible polymorphisms, once identified, will also vary by ethnicity. Evidence that these linkages can be reproduced range from outright independent confirmation (1q41, 4p16 and 6p21) to additional suggestive evidence in the genomic region of the purported linkage (1q22-23 and 2q37). The results now available suggest that human lupus genetics are robust and that gene identification should be possible using existing genetic approaches and technologies.

Hypomanic personality, social anhedonia and impulsive nonconformity: evidence for familial aggregation?

Schizophrenic and affective spectrum disorders aggregate in the families of patients afflicted with such disorders. Possible vulnerability markers for these disorders should therefore also run in families. The Chapmans and their coworkers developed the Hypomanic Personality Scale (HYP) to identify people at risk for affective disorders, and the scales Social Anhedonia (SA) and Impulsive Nonconformity (IMP) to assess schizotypy (Chapman et al., 1976, 1984; Eckblad & Chapman, 1986). The present family study investigated the familial resemblance of the HYP, SA, and IMP Scale using a maximum-likelihood approach. Index participants and their relatives (n = 717) completed a questionnaire packet that included the above-mentioned scales. Stepwise several models of familial correlations were specified and tested dealing with the influence of sex of parents and offspring and of interindividual cross-trait resemblance. For all three measures, there was evidence of familial resemblance. For SA and IMP, we found hints for possible assortative mating; additionally for HYP and IMP, an interindividual cross-trait resemblance (with correlations of 0.14 and 0.18, respectively) between family members emerged. The results support the validity of the HYP, SA, and IMP Scale. It is discussed whether HYP and IMP represent different aspects of a shared latent liability.