Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases.

OBJECTIVES: Severe alpha 1-antitrypsin (A1AT) deficiency is the one proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Familial aggregation has been demonstrated for COPD among individuals who do not have A1AT deficiency, but linkage analysis of COPD has not been reported. To investigate the optimal phenotype definitions and analytical methods for the linkage analysis of COPD, we examined a set of 28 A1AT- deficient families containing 155 individuals. We have used the protease inhibitor (PI) type as a genetic marker rather than a disease gene, and we have performed linkage analysis between PI type and serum A1AT level and spirometry-related phenotypes. METHODS: Linkage analysis was performed on the quantitative phenotypes forced expiratory volume at 1 s (FEV(1) as % predicted), the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC as % predicted), and serum A1AT level using the variance component approach in SOLAR, the generalized estimating equation approach in RELPAL, and the model-based classical lod score method in LINKAGE. Linkage analysis with qualitative A1AT and spirometry phenotypes was performed using a model-based method (LINKAGE) and a model-free method (GENEHUNTER). Adjustments for smoking effects were investigated under each method. RESULTS: All of the methods demonstrated linkage of PI type to serum A1AT level. Interestingly, however, the other quantitative phenotypes provided only weak evidence for linkage of PI type to lung disease. Better evidence for linkage of lung disease to PI type was found using a moderate or a mild threshold for the definition of airflow obstruction. CONCLUSIONS: For linkage analysis of spirometry phenotypes in A1AT deficiency, qualitative phenotypes provided stronger evidence for linkage than quantitative phenotypes. Possible contributors to the stronger evidence for linkage to qualitative spirometry phenotypes include the ascertainment scheme and the nonnormality of the pulmonary function data in PI Z subjects. This study provides guidelines for studies of the genetics of COPD unrelated to A1AT deficiency.     

Smoking and intermediate alpha1-antitrypsin deficiency and lung function in middle-aged men.

Lung function was evaluated in a representative population sample of 50-year-0ld men living in one Swedish city. Twenty-four smoking and 15 non-smoking men heterozygous for alpha1-antitrypsin deficiency--that is, with the protease-inhibitor (Pi1 phenotype MZ--were carefully matched for weight and smoking habit with Pi M controls. The pulmonary function of non-smoking Pi MZ subjects did not differ from that of non-smoking Pi M controls. In contrast, smoking heterozygotes showed a significant loss of elastic recoil, enlarged residual volumes, and increased closing capacity but no signs of obstructive ventilatory impairment. Most smoking Pi MZ individuals reported mild exertional dyspnoea.     

A comparative analysis of biomass and clean fuel exposure on pulmonary function during cooking among rural women in Tamilnadu,India

It is of interest to document data on the comparative analysis of biomass and clean fuel exposure on pulmonary function during cooking among rural women. The study consisted of 100 biomass and 100 LPG fuel using women with no smoking habits and other related illness Parameters such as FVC, FEV1, FEV1/FVC, PEFR, FEF25-75%were obtained using the computerized spirometry to assess the pulmonary function in these subjects. The collected data were analyzed using the Student t-test method and Pearson correlation. The exposure index for biomass fuel users is 69.78±27.25 showing high exposure duration during cooking. The parameters for pulmonary functions significantly declined in FVC (42.34±13.6), FEV1 (45.55±15.98), PEFR (34.11±14.78) and FEF25-75% (45.56±23.00) for biomass fuel user. However, this is not true for FEV1/FVC ratio (107.56±16.9). The increase in PFT suggests the restrictive and obstructive patterns of pulmonary diseases. There was a negative correlation between increased duration of cooking and the value of FEV1/FVC (r = -0.2961), FEF25-75% (r = -0.3519) and PEFR (r = -0.2868). Thus, the deformation of pulmonary function due to extended exposure of biomass fuel for cooking women in rural Tamilnadu is shown using parameter features such as high exposure index, overcrowded area and improper ventilated houses.     

Inheritance of extreme overweight in black families

We used complex segregation analysis to compare the genetic transmission of overweight in randomly selected black (N = 60) and white (N = 961) families. In both groups we found evidence for polygenic transmission. Major gene inheritance was strongly supported in whites and was marginally supported in blacks. Parameter estimates for black and white families were similar, suggesting that overweight is similarly transmitted in the black and white families we observed. There was evidence in both black and white families for high gene frequency and recessive gene expression. Extreme phenotypes common in black families may be the result of interactions between major genotype and polygenic or environmental factors; alternative explanations for differences in black and white families' transmission patterns are discussed. Replication with a larger group of black families is needed to confirm our findings.     

Common major gene inheritance of extreme overweight

We studied 3925 individuals in 961 families to determine the mode of inheritance of overweight. As an index of overweight, we examined body mass index. Our analyses indicate that the most likely genetic model for susceptibility to overweight included moderate polygenic inheritance (34% of variance resulting from many genes with small effects) and common (21% frequency) recessively expressed major genes (a few genes with large effects on the individuals who possess them). Standard statistical criteria for accepting both polygenic and major gene inheritance were met, including tests of Mendelian transmission. These results suggest that recessive major gene inheritance of overweight may be common and that homozygosity for overweight susceptibility alleles often results in overweight. Clinical, biologic, and empirical observations all suggest genetic heterogeneity, that is, more than one predisposing gene.     

On the genetics of the Pi serum proteins

Summary The authors report family studies (51 families with 134 children) on the inheritance of the Pi phenotypes. Combining these data with a Norwegian family material (77 families with 323 children) published by Fagerhol and Gedde-Dahl (1969) a total of 128 families with 457 children is now available, which allows the following conclusion: The Pi phenotypes are inherited by a simple codominant mode of heredity and they are determined by a set of (at least nine) alleles. As up to now no exception to the role of inheritance has been observed, the application of the Pi system in cases of disputed paternity seems to be discussible. Some methodological problems in connection with this are shown.Supported by the Deutsche Forschungsgemeinschaft.     

Segregation distortion of the alpha 1-antitrypsin Pi Z allele.

alpha 1-antitrypsin (alpha 1AT) of the Pi type Z is associated with two diseases: pulmonary emphysema and cirrhosis of the liver. We report 23 families with both parents heterozygous for the PiZ allele, characterized from our own analysis and from world literature sources. All families were identified through members expressing disease. From the extended pedigrees, 18 backcross families (parents with Pi types MM and MZ) were identified. Analysis of the backcross families reveals a significant increase in Pi MZ offspring (.73) among families where the male is heterozygous. The distortion is not detected among families where the female is heterozygous. Among the matings where both parents are heterozygous, we found 0.43 Pi ZZ from families where one or more members expressed hepatic cirrhosis, and 0.40 Pi ZZ for total families studied. This contrasts to the 0.25 Pi ZZ expected, but is consistent with the distortion observed in backcross matings. The implications of various statistical approaches are discussed, and we point out why our findings differ from previous reports. We suggest a possible biological explanation residing in the fertilization process.     

Heritability of lung function in severe alpha-1 antitrypsin deficiency

Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV1/FVC demonstrated significant heritability (0.26 +/- 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV1 demonstrated significant heritability (0.47 +/- 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV1 decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.     

Pulmonary emphysema associated with the FZ alpha 1-antitrypsin phenotype.

In one family three brothers were found to have a moderate deficiency of alpha 1-antitrypsin associated with the unusual Pi (protease inhibitor) phenotype FZ. The Pi phenotypes of their six living siblings were found to be FM (in three), M (in two) and MZ (in one). The three FZ brothers all had moderate to severe obstructive airways disease, and two had at least moderately severe pulmonary emphysema. Additional risk factors included moderate cigarette smoking in two and prolonged exposure to grain dust in all three. The same risk factors applied to the six non-FZ siblings, but they had only mild symptoms and pulmonary dysfunction or no lung problems at all; one, a female smoker with the MZ phenotype, had probable early emphysema demonstrated radiologically. The three FZ men may have had reduced fertility, as they produced only 1 child among them, as compared with 39 among the other eight siblings. This family study thus suggests that individuals with the FZ phenotype are at risk for pulmonary emphysema and chronic obstructive airways disease, particularly in the presence of other risk factors, such as cigarette smoking and grain dust exposure.     

Major gene detection for fusiform rust resistance using Bayesian complex segregation analysis in loblolly pine

The presence of major genes affecting rust resistance of loblolly pine was investigated in a progeny population that was generated with a half-diallel mating of six parents. A Bayesian complex segregation analysis was used to make inference about a mixed inheritance model (MIM) that included polygenic effects and a single major gene effect. Marginalizations were achieved by using Gibbs sampler. A parent block sampling by which genotypes of a parent and its offspring were sampled jointly was implemented to improve mixing. The MIM was compared with a pure polygenic model (PM) using Bayes factor. Results showed that the MIM was a better model to explain the inheritance of rust resistance than the pure PM in the diallel population. A large major gene variance component estimate (> 50% of total variance), indicated the existence of major genes for rust resistance in the studied loblolly pine population. Based on estimations of parental genotypes, it appears that there may be two or more major genes affecting disease phenotypes in this diallel population.     

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.     

Complex segregation analysis of non-myoclonic idiopathic generalized epilepsy in families ascertained from probands affected with idiopathic epilepsy with tonic-clonic seizures in Antioquia,Colombia

In an attempt to identify the possible role of major genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic-clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single major locus (dominant and recessive) only, and multifactorial component only, were rejected. Since the codominant single major locus model could not be rejected and models that assign no major locus to transmission, no polygenic component to transmission, and no transmission of the major effect were rejected, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explained clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to the polygenic component. Received: 19 January 1996 / Revised: 11 March 1996     

Complex segregation analysis of canine hip dysplasia in German shepherd dogs

Complex segregation analyses were carried out to clarify the mode of inheritance of canine hip dysplasia (CHD) in German shepherd dogs. Data were used from 8,567 animals examined for CHD from 20 families with three to four generations. The existence of a major gene in addition to polygenic gene effects was detected. In the present study, a mixed model with a dominant major gene effect seemed to be most probable for dichotomous encoding (0: dogs without signs of CHD; 1: dogs with borderline/slight to severe CHD). In addition, mixed major gene inheritance was shown for a binary trait where borderline was assigned to dogs scored free from CHD and for a trichotomously encoded trait (0: dogs without signs of CHD; 1: borderline CHD; 2: mild to severe CHD). Although only small frequencies were found for the unfavorable homozygotic genotype AA, the probability of the AB genotype was high in affected animals. Selection schemes to reduce the frequency of the allele A should therefore efficiently improve existing breeding programmes in German shepherd dogs.     

Segregation analysis of schizophrenia and related disorders

Segregation analysis was applied to 79 nuclear families ascertained through chronic schizophrenic probands. Analysis was performed on the diagnosis of schizophrenia alone and on schizophrenia and schizotypal personality disorder (milder phenotype) combined. The models used were the transmission probability model and the mixed model. Because the disease is associated with reduced fertility, all likelihoods were calculated conditional on parental phenotypes. However, compatibility of the mating-type distribution predicted by each model with the observed was also examined. In all analyses, results suggested consistency with genetic transmission. In the analysis of schizophrenia alone, discrimination among models was difficult. In the analysis including the milder phenotypes, all single-locus models without polygenic background were excluded, while pure polygenic inheritance could not be eliminated. The polygenic model also gave good agreement with supplementary observations (lifetime disease incidences, mating-type distribution, and monozygotic twin concordance). The estimated components of variance for the polygenic model were: polygenes (H) 81.9%; common sib environment (B) 6.9%; random environment (R) 11.2%. Although the polygenic model was parsimonious, segregation analysis and the supplementary observations were also consistent with a mixed model, with a single major locus making a large contribution to genetic liability. Such a locus is more likely to be recessive than dominant, with a high gene frequency and low penetrance. The most likely recessive mixed model gave the following partition of liability variance: major locus, 62.9%; polygenes, 19.5%; common sib environment, 6.6%; and random environment, 11.0%.     

Effects of the multiple risk factor intervention trial smoking cessation program on pulmonary function. A randomized controlled trial.

To determine whether the decline in pulmonary function in smokers is modified by stop-smoking intervention, a randomized controlled study (the Multiple Risk Factor Intervention Trial) was done comparing participants in a special intervention group that included an intensive smoking cessation program with those assigned to usual care. The subjects were 6,347 middle-aged male smokers who had serial measurements of pulmonary function--principally the forced expiratory volume in 1 second (FEV1)--during 6 to 7 years of follow-up. No overall differences were detected in the rate of loss of FEV1 in the two groups. The use of beta-blockers, which had detrimental effects on FEV1, was significantly more common in the intervention group. Among nonusers of beta-blockers, heavy smokers lost FEV1 at a rate about 11 ml per year slower in the intervention group than in the control group (2P = .09) and ended the trial with an FEV1 about 90 ml higher (2P = .05). These results support the inference from observational studies that smoking cessation has a beneficial effect on pulmonary function in heavy smokers.     

Effects of prematurity and intrauterine growth on respiratory health and lung function in childhood.

OBJECTIVE--To determine whether birth weight and gestational age are associated with respiratory illness and lung function in children aged 5-11 years. DESIGN--Cross sectional analysis of parent reported birth weight, gestational age, and respiratory symptoms; parental smoking and social conditions; forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory rates between 25% and 75% and 75% and 85% (FEF25-75 and FEF75-85), and height. SETTING--Primary schools in England and Scotland in 1990. SUBJECTS--5573 children aged 5-11 (63.3% of eligible children) had respiratory symptoms analysed and 2036 children (67.1% of eligible children) had lung function measured. MAIN OUTCOME MEASURES--Symptoms of asthma, bronchitis, occasional and frequent wheeze, cough first thing in the morning, and cough at any other time and lung function. RESULTS--Birth weight adjusted for gestational age was significantly associated with all lung function measurements, except FEF25-75. The association remained for FVC (b = 0.475, 95% confidence interval 0.181 to 0.769) and FEV1 (b = 0.502, 0.204 to 0.800) after adjustment for gestational age, parental smoking, and social factors. FEF75-85 was the only lung function related to gestational age. Respiratory symptoms, especially wheeze most days (adjusted odds ratio 0.9, 0.84 to 0.97) were significantly associated with prematurity. Every extra week of gestation reduced the risk of severe wheeze by about 10%. CONCLUSIONS--Lung function is affected mainly by intrauterine environment while respiratory illness, especially wheezing, in childhood is related to prematurity.     

A family study of dermatoglyphic traits in India: resolution of genetic and uterine environmental effects for palmar pattern ridge counts

The inheritance of palmar pattern ridge counts for individual palmar areas, combined distal areas, and all ten areas combined was investigated in families belonging to two strictly endogamous Brahmin castes of peninsular India. Ridge count phenotypes were obtained by the method proposed by Malhotra et al. (1981a), however, zero observations (indicating patterns not circumscribed by triradii) were excluded from analysis. Path analytic methods were applied in order to determine the relative influences of polygenes, intrauterine environment, and residual environment. The proportion of genetic variation was, in general, consistently greater in one population than the other, and significant intrauterine environmental effects were detected for the population with lower heritabilities. The results of this investigation suggest that a simple polygenic model may not be sufficient to explain the inheritance of ridge counts in the interdigital IV configurational area. Distal pattern ridge counts do not appear to be influenced by more or less uterine environmental effects than all areas considered together. The proportion of genetic variation for the total palmar pattern ridge count was 52% in both populations.     

The Use of Mixture Models to Detect Effects of Major Genes on Quantitative Characters in a Plant Breeding Experiment

An analysis based on Elston's model of mixed major locus and polygenic inheritance is extended to include populations of progeny testing such as F(3), B(1s) and B(2s) families derived from F(2) and backcrosses in a cross between two inbred lines. Genetic hypotheses that can be validly tested by the likelihood ratio method in the analysis of a breeding experiment include homogeneity of variances due to environment and/or polygenes with transformable scale effect by Box-Cox power function, random and independent segregation of major genes, invariance of the effects of major genes with population types and additive and dominant models for polygenes. Testing hypotheses in the order suggested here can lead to a gradual simplification of the models and increases the feasibility of the subsequent analysis, but caution must be paid to the possible bias in parameter estimation and hypotheses tests. The procedure is applied to a set of data on plant height of rice with the effects of dwarf genes in crosses among three varieties. Two recessive dwarf genes are shown to be nonallelic and unlinked. One dwarf gene is shown to reduce plant height about 36-56 cm, and another 52-61 cm. The effect of polygenes, estimated as the standard deviation among possible inbred lines derived from these crosses, is about 11.7 cm. Interactions between the dwarf genes and the polygenic background are found, especially for one of the two genes. Both the polygenic effects and the interactions are much smaller than the effects of the major dwarf genes.     

The effect of cultural transmission on continuous variation.

Cultural transmission may depend on the non-genetic transfer of information from parent to offspring. The consequences of such cultural transmission for continuous variation are investigated theoretically for randomly mating populations. Cultural inheritance may act on genetical and environmental differences between individuals. The consequences for cultural inheritance of polygenic variation and variation due to chance environmental factors are considered. An equilibrium may occur in which the population variance and the covariances between relatives can be expressed as functions of estimable parameters of genetical and environmental variation. Whatever the ultimate origin of culturally inherited differences they are expected to lead to environmental differences between families ("E2" variation). In addition, if cultural transmission maintains differences due ultimately to segregation at many gene loci we may find genotype-environmental covariation is generated.     

Multifactorial inheritance with cultural transmission and assortative mating. III. Family structure and the analysis of separation experiments.

Demographic data about family composition or structure in the United States is reviewed. About 25% of white children and a majority of black children are reared in either broken or extended families, and this must be taken into consideration for valid studies of cultural inheritance. Atypical family structures are described including those in which parents include: biological parents, stepparents, grandparents, uncles, aunts, sibs, foster parents, and their spouses. General formulae for a wide variety of kinship correlations are derived using path analysis. The multifactorial model presented allows for cultural inheritance, polygenic inheritance, correlated sibling environments, and phenotypic assortative mating (as previously described for intact families) plus extensions necessary for the analysis of separation experiments. These extensions allow for variable family structure and differences in parental influence due to separation, age or stage of development of the child, birth order, or type of relationship. Family structure is observed to have a marked effect on familial resemblance. Computer simulation studies demonstrate marked heterogeneity among phenotypic correlations for kinships of the same degree of genetic relationship arising in different family structures. Analyses of multiple types of sibs and other relatives in variable family structures offer great promise for the study of cultural inheritance.