Drinking style of parents of alcoholic and control probands

One aspect of the familial component of alcoholism is the use of alcohol among the parents of affected individuals. Both the individual and concordant drinking styles of the parents of 291 inpatient alcoholic probands and 71 non-alcoholic control subjects were measured using family history methods. Social drinking was almost twice as prevalent among fathers of controls compared to fathers of alcoholics. Problem drinking was more than twice as prevalent among the fathers of alcoholics compared to fathers of controls. The abstinence rate for fathers of both groups was similar. Mothers' drinking styles were similar to the fathers' pattern for both groups. Concordance of drinking style in the parental pair was examined. Similarity in drinking style for the parents of control probands was greatest for social drinking. For parents of alcoholic probands high concordance was also found by problem drinking. Overall a great similarity in drinking style was found for the parents of control probands compared to the parents of alcoholic probands.     

Structural decomposition of genetic diversity in families with alcoholism

Using genotypes of 280 marker loci on the 22 autosomes of 105 alcohol-dependent probands, their affected and unaffected sibs, as well as their parents, we iteratively constructed a genetic similarity function that enabled us to quantify the interindividual genetic distances d(x(i), xj) between feature vectors x(i), xj made up by the allelic patterns of individuals i, j with respect to loci l1, l2,...,ln. Based on this similarity function, we investigated the sib-sib similarities that are expected to deviate from "0.5" in affected sib pairs if the region of interest contains markers close to disease-causing genes. The reference value "0.5" was derived from the parents-offspring similarities, because these are independent of the affection status. The question of population admixture was addressed by means of multivariate structural analyses. These analyses led to four "natural" groups whose validity was tested through the father-mother similarities. Additionally, we determined the eigenvectors that optimally represented the genetic variation and found several marker configurations on chromosomes 1, 3, 7, 15, and 17 that reproducibly discriminated (p < or = 0.01) affected probands/sibs from unaffected sibs, while no such differences were found between affected probands and affected sibs.     

Availability of schizophrenic patients and their families for genetic linkage studies: findings from the Maryland epidemiology sample

It has been suggested that collections of affected sib pairs, or their nuclear families, may be an efficient method for screening for genetic linkages in schizophrenia. We present the data collected in five years from 15 hospitals in the state of Maryland in an effort to determine if such a collection scheme will be feasible. Probands in our sample were eligible for inclusion in the sample if they were white, were age 16 years or older, and carried a research diagnosis of schizophrenia. Family data are reported for 258 probands. Using the most stringent category of affected (RDC schizophrenia) revealed ten families with two or more affected sibs. The broadest category of affected (any psychotic disorder or psychiatric hospitalization) identified only 36 families with two or more affected sibs. We conclude that, if schizophrenia is a heterogeneous disorder with decreased penetrance, an effort to collect multiplex nuclear families is unlikely to provide enough data to identify genetic linkage. Alternatively, an effort to seek out and collect larger multiplex, multigenerational families rather than a collection of affected sib pairs may be more efficacious.     

HLA antigens and acute rheumatic fever: evidence for a recessive susceptibility gene linked to HLA

From 60 probands with acute rheumatic fever (ARF), 19 multiplex families segregating for ARF were ascertained. The parents and rheumatic and normal sibs of the probands in these 19 families were also studied. HLA typing using the microlymphocytotoxic assay was then performed on the 60 unrelated probands, the multiplex families, and 234 unrelated controls using 23 antigens from the HLA-A and -B loci. The controls lacked a past history of ARF and were from the same geographic locality. Calculations of relative risk demonstrate an increase of HLA-B5 antigen in the 60 patients, but the result might not be significant from the point of view of multiple comparisons. Nevertheless, affected sib pairs from the multiplex families show 93% concordance for both or one HLA haplotype. A formal linkage analysis demonstrates that a recessive etiology is most likely (lod score of 3.3) with approximately 68% of cases being due to a gene closely linked to HLA and in linkage disequilibrium with HLA-B5. The remaining 32% of cases are due to other familial factors such as polygenic inheritance or common environmental factors. The results confirm a strong genetic predisposition to ARF and its heterogeneous nature in families.     

P300 from normals and adult children of alcoholics

The P300 event-related brain potential (ERP) was obtained from 24 pairs of undergraduate male subjects. One member of each pair reported having a father who was alcoholic (FH+), the other reported no alcoholic family member (FH-). Pairs were matched on height, weight, academic performance, and personal drinking history. Three auditory task situations were employed which manipulated stimulus discrimination difficulty. All tasks employed 20% target and 80% standard tones randomly presented with the subjects required to move their index finger whenever a target tone was detected. No differences in P300 amplitude or latency were obtained between the groups. FH+ subjects tended to demonstrate decreased amplitudes with increased amounts of reported alcohol consumption but only for the most difficult task. The results of the present study suggest that the relationship between the P300 and the heritability for alcoholism is not yet clear and may be modulated by differences in task requirements, subject populations, and personal drinking history.     

Familial risk ratio of sarcoidosis in African-American sibs and parents

While sarcoidosis is thought to aggregate in families, little is known about the risk to relatives of sarcoidosis patients. To estimate the familial risk ratio (lambda) of sarcoidosis in sibs and parents of cases, the authors studied 179 African-American families ascertained through an index sarcoidosis case diagnosed at Henry Ford Hospital in Detroit, Michigan. Among those relatives enrolled between 1997 and 1999, 12 of 327 (3.7%) sibs and 11 of 161 (6.8%) parents reported a history of sarcoidosis. The lambda in this sample of relatives, estimated by computing an age, sex, and race standardized incidence ratio, was 2.24 (95% confidence interval: 1.16, 3.92) for sibs and 2.82 (95% confidence interval: 1.41, 5.05) for parents. For sibs and parents combined, lambda was 2.49 (95% confidence interval: 1.58, 3.73). Results stratified by proband characteristics indicated that lambda was greater for relatives of younger (lambda = 2.93, 95% confidence interval: 1.52, 5.12) and male (lambda = 3.98, 95% confidence interval: 1.99, 7.12) probands. A higher lambda was also found for male family members and sibs born later in the birth order. A Monte Carlo method was also used to estimate lambda, with similar results obtained. Overall, these results indicate that, in African Americans, sibs and parents of sarcoidosis cases have about a 2.5-fold increased risk for sarcoidosis and that heterogeneity in disease risk may exist among family members.     

Assessing the Effect of Sampling Strategies on the Power of Linkage Analysis to Identify Pathway‐Specific Loci Underlying a Complex Disease

Using the simulated general population data sets, we first examined the effect of sampling strategies on the power of identifying linkage by selecting samples with (A) two affected sibs in a nuclear family and (B) one affected sib and one sib with an intermediate trait value in the upper quantiles. Second, we evaluated the improvement in power when analyzing correlated traits simultaneously. Under each selection criteria, 100 replicates of 300 nuclear families were sampled and analyzed with two‐point linkage analysis for ten markers (1 cM apart) from each of the candidate regions. Different genes were identified under different sampling strategies. When a gene has a pleitropic effect, it is more powerful to analyze correlated traits simultaneously, either by using a linear combination or the larger value of standardized traits, than to analyze each trait separately. © 2001 Wiley‐Liss, Inc.     

Family risk factors of alcoholism and drinking patterns among non alcoholic women: an inverse relationship? An exploratory study of female employees

95 non alcoholic female employees were personally interviewed and divided into three drinking pattern groups with an increasing level of alcohol consumption: the traditional feminine drinking group (TF) (n = 28), the new feminine drinking group (NF) (n = 37), and the masculine drinking group (M) (n = 30). The groups were compared on family variables which may be regarded as risk factors of alcoholism. The results show an inverse relationship between family risk factors and consumption level, the TF-group having significantly more risk factors than the other two groups. The TF-women more often came from families where the mother and her parents were abstainers, while the father and his parents were more often alcohol abusers or not abstainers. The TF-women were more often attached to their alcoholic fathers as children, while the M-women were more often attached to their mothers. The choice of drinking pattern may be inversely related to the frequency of family risk factors among non alcoholic women.     

The importance of watching our weights: how the choice of weights for non-independent sib pairs can dramatically alter results

Handling non-independent sib pairs in families with multiple affected sibs presents a problem in likelihood-based nonparametric linkage analyses. We contrast the more stable partial-likelihood solution in MAPMAKER/SIBS with the extremely variable partial-likelihood approach used in ASPEX, and the potential inflation of lods when the problem is ignored as in BETA.     

Relative-risk regression models using cases and their parents

Relative-risk regression models are presented for studies of the association of genetic markers with disease status when the study design uses affected cases and their parents, with or without unaffected sibs. These models generalize the “haplotype relative-risk” method and allow for censored unaffected sibs; in this sense, these models resemble proportional hazards models that are commonly used in survival analysis. A critical distinction between these models and the usual Cox proportional hazards model is that the frequencies of the genotypes of the cases are compared to controls based on Mendelian expectations, and not simply to the genotypes of the sib controls who are at risk of disease. These models allow modeling of the contribution of specific alleles to the relative risk of disease, as well as interactions of allelic effects with environmental risk factors. To demonstrate the application of these models, we have fit them to the binary affection status of the Problem 2 data set. Four candidate-gene loci were found to have a significant association with affection status, after allowance for relative risks that decrease with age; two of these associations correctly identified two of the major gene loci, and the other two were false-positive associations. © 1995 Wiley-Liss, Inc.     

Etiologic heterogeneity in alcoholism

Etiologic heterogeneity in alcohol abuse was evaluated in 195 extended pedigrees, comprising 288 nuclear families of 140 male and 55 female Caucasian American hospitalized alcoholics. Previous adoption studies in Sweden demonstrated differential heritability of two patterns of alcohol abuse in men: type-2 alcoholism exhibited early onset of abuse associated with criminal behavior, while type-1 abuse began at a later age, uncomplicated by antisocial traits. Alcohol abuse in female Swedish adoptees was relatively homogeneous and similar to the late-onset, type-1 abuse. The notion of etiologic heterogeneity, as suggested by the Stockholm Adoption Studies, was examined in the American pedigrees by contrasting the models of familial transmission of susceptibility to alcoholism obtained via segregation analyses of families of male versus female probands. Families of male probands demonstrated significant familial resemblance, accounted for by a multifactorial-polygenic background in addition to a major (gene) effect. In contrast, familial resemblance in the pedigrees of female probands was attributed solely to a multifactorial-polygenic effect. We considered whether some families of male alcoholics were similar to families of female probands, who expressed type-1 abuse predominantly. Pedigrees of male probands were separated in two groups: (1) "female-like" families had a better likelihood for the model obtained for families of female probands than the one for families of all male probands, (2) "male-like" families had a better likelihood for the model of familial transmission describing families of all male probands. A statistically significant difference in the pattern of familial transmission was observed between the "male-like" and "female-like" groups. Discriminant function analysis of alcohol-related symptoms showed that the familial subtypes differed in clinical features as well. Alcohol abuse by male relatives in "male-like" families was characterized by the early onset of inability to abstain entirely from alcohol or lack of desire to stop drinking; in contrast, abuse in "female-like" families was characterized by late onset of guilt feelings and loss of control over binge drinking.     

Detection of major genes underlying several quantitative traits associated with a common disease using different ascertainment schemes

Using the Problem 2A data sets of GAW10, we assessed the power of four ascertainment schemes to localize major genes underlying a disease trait; the schemes were based on disease or quantitative trait status of nuclear families. MAPMAKER/SIBS was used to perform sib-pair analysis for all four data sets using marker data from three chromosomes, 4,5 and 8. Each scheme varied in power to identify major genes underlying the quantitative traits depending on the genetic architecture of the data set. Three different methods, Haseman-Elston quantitative trait locus (QTL) regression analysis, maximum likelihood variance estimation and a non-parametric method, were used to assess the strength of linkage in all four data sets. False positive mappings localizing to the same region of the genome, verifiable across all three methods did not occur. Two major genes, MG1 and MG2, were successfully assigned to chromosomes 5 and 8, respectively, by at least one of the ascertainment schemes. MG1 was localized under two schemes, selection of families with exactly two affected sibs and selection of families with two sibs who had extremely discordant values for Q1. Additional weak evidence of the location of MG1 was also obtained under the other two ascertainment schemes. MG2 could not be detected by analyzing data sets ascertained either by affected sib pairs or by sib pairs with extremely discordant values for Q1. In the data set ascertained by a third strategy, selection of families with sib pairs extremely discordant for Q2, MG2 could be mapped to chromosome 8. A random ascertainment scheme yielded a data set in which we could find weak evidence for MG1 and no evidence for MG2. Thus our ability to detect major genes underlying the QTL depended on several factors which included the ascertainment scheme, the population allelle frequencies, linkage and epistasis. © 1997 Wiley-Liss, Inc.     

Efficient use of siblings in testing for linkage and association

Tests of linkage and association between a disease and either a candidate gene or marker allele can be based on sibships with at least one affected and one unaffected sibling. However, specialized techniques are required to account for within-sibship correlation if some sibships contain more than one affected or more than one unaffected sib. In this paper, we propose Within Sibship Paired Resampling (WSPR), a technique that is designed to test the null hypothesis of no linkage or no association, even when sibships contain variable numbers of sibs. One repeatedly generates data subsets based on randomly sampling one affected and one unaffected sibling from each sibship, and each subset is analyzed individually. Then, evidence is combined by averaging results across these resampled data sets, applying a variance expression that implicitly accounts for the correlation among siblings. While the general WSPR procedure allows for numerous testing strategies, we describe two in detail. Simulation results for scenarios with varying degrees of population stratification demonstrate good power for the WSPR testing methods compared to the sib TDT (S-TDT) and the sibship disequilibrium test (SDT).     

The mode of inheritance of blood pressure levels.

In a sample of 465 families living in a suburb of north-west London the systolic and diastolic blood pressure consistently showed a greater correlation for sib/sib (0.16 to 0.28) than for parent/offspring (0.07 to 0.18); this pattern is consistent with the hypothesis of a dominance component in the inheritance of blood pressure assuming there is no difference in the interaction between environment and genes in people of different ages. This assumption was examined by studying the sib/sib correlation according to the age gap between sibs; for diastolic blood pressure this remained almost the same but for systolic blood pressure the correlation tended to diminish as the age gap increased. A dominance component in the inheritance of blood pressure levels could explain the sort of results we have found in this study. However, we cannot ignore the fact that similar results could be obtained if the contribution of the environment within the same generation of relatives differs from that of the environment shared by all relatives.     

Recurrence risk for major congenital heart defects in Sweden: A registry study

During the period 1981–1986, 1605 infants presenting a major congenital heart defect (CHD) were identified in Sweden. Using the personal identification numbers of the mothers, 1507 of them could be linked to the Medical Birth Registry and two controls were selected for each infant. For this total of 4521 infants, 2686 postoccurrence sibs born during the period 1981–1989 were identified from the Medical Birth Registry. The tendency to have one or more sibs was higher among cases than among controls and was correlated to the life status of the proband. This tendency did not vary according to the type of CHD when controlling for life status. The prevalence at birth of CHD was almost four times higher among sibs of CHD infants than among sibs of normal infants. The tendency to have a sib with an extracardiac malformation did not differ between CHD probands and normal probands. The importance of only including births occurring after the proband when evaluating recurrence risks is stressed. © 1994 Wiley-Liss, Inc.     

Likelihood-ratio affected sib-pair tests applied to multiply affected sibships: issues of power and type I error rate

"All-pairs" likelihood-ratio analyses, such as those performed by MAPMAKER/SIBS [Kruglyak and Lander, 1995], require that a sibship containing N affected siblings be split into N(N - 1)/2 sibships, each containing a different pair of affected sibs, before analysis. Each of these N(N - 1)/2 sibships may also contain the other affected sibs from the original sibship, coded as unaffected, to infer missing parental genotypes, as is done automatically in MAPMAKER/SIBS. Then, the use of the same individuals both as affecteds to test for linkage and, elsewhere, as unaffecteds to infer missing parental genotypes leads to negative correlations in the estimated identity by descent sharing among affected pairs from the same original multiplex sibship. This gives a conservative test of linkage, even when no downweighting is applied. Conversely, if the other affected sibs from the original sibship are omitted, the correlations are positive and the linkage test is anticonservative in the absence of weighting. True type I error probability also depends on marker informativity, typed parents, number of affected sibs included in the analysis, and the weighting scheme. This suggests the use of simulation, rather than asymptotic theory, to assess significance levels. The power of multiplex sibships relative to affected pairs increases with increasing phenocopy percentage, but the presence of typed unaffected sibs improves the relative power of multiplex sibships greatly only when penetrance is high. It was found that the 2/N weighting proposed by Suarez and Hodge [1979] increased power over an unweighted analysis in many situations, provided significance levels were adjusted appropriately by simulation.     

To Type or Not To Type: The Use of Unaffected Siblings in Nonparametric Linkage Analysis

Unaffected individuals are often disregarded in nonparametric linkage analysis. Because of the presumed high complexity of genetic interactions and the resulting low penetrance of any single genetic effect, the statistical contribution of unaffected sib pairs is thought to be considerably lower than that of the affecteds. However, in cases where a large number of unaffected family members are available for genotyping — as is the case in the simulated Genetic Analysis Workshop 12 data set — the relatively low value of the unaffected sibs may be offset by their number. In this paper, I demonstrate that unaffected siblings do contain a significant amount of statistical information, and show that the most powerful method of nonparametric analysis utilizes both affected and unaffected individuals. I also show that selecting the unaffected individuals based on their age is the most cost effective and usually the most powerful strategy. © 2001 Wiley‐Liss, Inc.     

Mental symptoms and disorders in adulthood among offspring of alcoholic parents

211 male alcoholic inpatients (the probands) were compared with a simple random sample of 200 men from Greater Stockholm (the controls). The group of male alcoholic inpatients and the random sample were subdivided with respect to alcohol consumption and use of hepatotoxic drugs: (IA) men from the random sample with low or moderate alcohol consumption and no use of drugs (n = 169); (IB) men from the random sample with low or moderate alcohol consumption with use of drugs (n = 31); (HA) alcoholic inpatients with use of alcohol but no drugs (n = 171); (MB) alcoholic inpatients with use of alcohol and drugs (n = 40). Groups IB and IIB had grown up in families with more abuse of alcohol and drugs, broken homes and an alcohol-abusing father. They showed aggressive behaviour and hostility towards members of their own families when drunk and had even assaulted their partners, wives and children. Groups IB and IIB had been drinking excessively for almost the same time and had an earlier onset, and both had also earlier used narcotic drugs and had the same, type of mental symptoms and mental disorders. They had the same rate of accidents, hospital treatment, poisoning and violence. The alcohol and drug-combining groups in the sample from the general population and from the alcoholic in-patients were equally likely to develop social maladjustment problems, including abuse of alcohol and drugs, while they were growing up.     

Event-related potentials in women at risk for alcoholism

Event-related potentials (ERPs) elicited during information processing tasks are useful for assessing brain function. Abstinent male alcoholics exhibit deficits in ERPs. The present study found that female alcoholics with early onset alcoholism (18.3 ± 1.3 years) showed significant deficits in P300 amplitude relative to both high-risk and low-risk controls. Two interpretations of these findings are possible. P300 amplitude reduction among the alcoholic women might be a neuropathological consequence of excessive drinking. Alternatively, lower amplitude of the P300 wave may be a marker for alcoholism risk segregating within high-risk families and associated with development of alcoholism. The later interpretation is favored based on the unlikely possibility that the nonalcoholic high-risk women would later convert to alcoholic status due to their age (mean age of 35.6 ± 1.6 years).     

Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred.

We examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA-linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA-DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P less than 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well-established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib-pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA-DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P less than 0.001). The same results were obtained by an independent method which considered HLA-DR transmission from affected parents to their affected children. The affected sib-pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA-linked locus on familiarity accounted for only a 1.61-fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non-HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.