Mendelian Major Gene Research Articles

Heritability and segregation analysis of osteosarcoma in the Scottish deerhound

Osteosarcoma is the most common malignant bone tumor in dogs and, like its human orthologue, is characterized by aggressive local behavior and high metastatic rates. The Scottish deerhound is a breed of dog with a >15% incidence of osteosarcoma and represents an excellent spontaneously occurring large-animal model of the human disease. We modeled the transmission of the osteosarcoma phenotype in a population of over 1000 related deerhounds ascertained as part of a prospective health study. Variance component analysis, segregation analysis, and linear modeling were performed to evaluate heritability, to infer the presumptive transmission model, and to identify covariate effects for this phenotype within the breed, respectively. Based on variance component analysis, heritability (h2) was estimated to be 0.69. Six transmission models were analyzed by segregation analysis; based on Akaike's information criteria, the most parsimonious model was the Mendelian major gene model with dominant expression. Linear modeling identified gender and genotype as significant predictors of disease outcome. Importantly, duration of gonadal hormone exposure, weight, and height at maturity were not significant predictors of outcome. Inheritance of the putative high-risk allele was thus associated with >75% risk of disease occurrence compared to the <5% baseline risk. These results support the hypothesis that a major gene with a dominant effect explains most of the osteosarcoma phenotype within the Scottish deerhound.

Major gene evidence after MTHFR-segregation analysis of serum homocysteine in families of patients undergoing coronary arteriography.

Elevated levels of homocysteine is a risk factor for coronary artery disease. Polymorphic alleles in the MTHFR genes that cause recessively inherited increased homocysteine level can explain only a small proportion of the observed variation in homocysteine level. To investigate additional genetic influences, we examined environmental, familial, and genetic influences on serum homocysteine levels in 661 family members of 112 probands who underwent elective coronary arteriography. Maximum likelihood methods were used to fit several genetic and non-genetic models of inheritance to these data to determine if an unobserved Mendelian major gene could explain the familial homocysteine distribution. Adjustments for age, lifestyle (smoking and alcohol consumption), serum folate and vitamin B12, and the measured genotype effect of the MTHFR C677T mutation was carried out separately for males and females using multiple regression models for homocysteine, before and after log-transformation prior to this segregation analysis. After excluding the effects of mutations in the MTHFR genes, we found evidence of a major gene acting in a co-dominant manner. Estimated mean homocysteine levels for the three putative genotypes (LL, LH, and HH) were 8.0, 10.1, and 15.9 micro mol/l, respectively, with relative frequencies of 56.8%, 37.2%, and 6%, respectively. Our analysis suggested the presence of a co-dominantly expressed major gene, in addition to the effects of the MTHFR C677T mutation. The results of this study also indicated that multifactorial inheritance was supported more strongly than Mendelian inheritance alone. Our findings may have implications for attempts to identify new homocysteine susceptible genes.

Segregation analysis of waist circumference, hip circumference and waist-to-hip ratio in the Korean Nationwide Family Study.

A central distribution of adipose tissue is frequently associated with cardiovascular disease and its risk factors. In this study, we investigated environmental, familial and genetic influences on waist circumference (WC), hip circumference (HC) and waist-to-hip ratio (WHR) in 2507 members of 435 families who had participated in the Korean Nationwide Health Examination Survey. Maximum likelihood methods were used to fit several genetic and nongenetic models of inheritance to these data to determine whether an unobserved Mendelian major gene could explain the familial distribution of WC, HC and WHR. Adjustments for age, age(2), body mass index, smoking, alcohol consumption and exercise were carried out separately for males and females by multiple regression procedures for WC, HC and WHR phenotypes prior to segregation analysis. Regression models were used to test genetic and non-genetic models in these 435 families. Segregation analysis did not provide statistical evidence of a major gene controlling either HC or WHR. Mendelian single-locus models with two underlying genotypic distributions were best supported by these data on WC, and this putative major gene explained the 22.4% of variance in adjusted WC. Future linkage studies may be worthwhile to further clarify the mechanisms controlling WC.

Genetic contribution to factor VII levels in families of patients undergoing coronary arteriography.

An elevated plasma level of factor VII is a risk factor for coronary artery disease. We investigated environmental, familial, and genetic influences on factor VII activity in 508 family members of 87 probands who underwent elective coronary arteriography. Maximum likelihood methods were used to fit several genetic and non-genetic models of inheritance to these data to determine whether an unobserved Mendelian major gene could explain the familial distribution of factor VII. Factor VII activities were adjusted for age, gender, body mass index, smoking, alcohol consumption, menopause status, and triglycerides prior to this segregation analysis (this model accounted for 33.5% of the total variation). Adjusted factor VII activities showed strong familial aggregation with an estimated parent-offspring correlation of 0.34, sibling correlation of 0.36 and a smaller spouse correlation of 0.16. Regressive models were used to test genetic and non-genetic models in these 87 families. Mendelian single-locus models with either two or three underlying genotypic distributions of factor VII activities were best supported by these data. Essentially, these Mendelian models suggest most individuals come from a low distribution (mean, 116%), with a few individuals homozygous for a high allele drawn from a distribution with a mean of 166%. Future linkage studies may be worthwhile to further clarify the mechanisms controlling factor VII activity.

Segregation analysis of serum uric acid in the NHLBI Family Heart Study.

Segregation analysis was performed on the serum uric acid measurements from 523 randomly ascertained Caucasian families from the NHLBI Family Heart Study. Gender-specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analysis. Uric acid residuals were adjusted for age, age2, age3, body mass index (kg/m2), creatinine level, aspirin use (yes/no), total drinks (per week), HOMA insulin resistance index [(glucose * insulin)/22.5], diuretic use (yes/no), and triglyceride level. Sibling correlations (r=0.193) and parent-offspring correlations (r=0.217) were significantly different from zero, but these two familial correlations were not significantly different from one another. After adjustment for covariates, the heritability estimate for serum uric acid was 0.399. Segregation analysis rejected the "no major gene" model but was unable to discriminate between an "environmental" and a "Mendelian major gene" model. These results support the hypothesis that uric acid is a multifactorial trait possibly influenced by more than one major gene, modifying genes, and environmental factors.

Evidence for major genes influencing pulmonary function in the NHLBI family heart study.

Segregation analysis was performed on the pulmonary measures forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the ratio of FEV1/FVC in 455 randomly ascertained families from the NHLBI Family Heart Study (FHS). Gender specific standardized residuals were used as the phenotypic variable in both familial correlation and segregation analyses. These residuals represented adjustments for the effects of age, age(2), age(3), Body Mass Index (BMI, kg/m(2)), height, the ratio of waist to hip measurements (WHR), the presence of coronary heart disease, smoking history, and pack years for current smokers. Sibling correlations were not different from parent-offspring correlations for all three traits, and heritability estimates for FEV1, FVC, and the FEV1/FVC ratio were 0. 515, 0.540, and 0.449, respectively. Segregation analysis of FEV1, a trait that measures airflow, indicated that a dominant major gene best fits the data, although a residual familial correlation supports the presence of an additional polygenic or common environmental component. For FVC, a trait that measures lung volume, alternative models could not be statistically differentiated, but the transmission probabilities do not support a Mendelian major gene. The best model for FEV1/FVC ratio is a non-Mendelian codominant model, perhaps due to the mixing of the individual underlying distributions influencing airflow and lung volume. These results support the hypothesis that complex relationships exist for lung function traits and that multiple genes and environmental factors influence lung function.

Patterns of parental transmission and familial aggregation models in bipolar affective disorder

Two recent studies [McMahon et al., 1995: Am J Hum Genet 56:1277-1286; Gershon et al., 1996: Am J Med Genet (Neuropsychiatr Genet) 67:202-207] reported an excess of maternal transmission in bipolar affective disorder in multiply affected families. In a sample of 130 families ascertained through a bipolar proband without regard to psychiatric family history we analysed the frequency of maternal (MAT) and paternal (PAT) transmissions, the morbid risk (MR) in relatives of transmitting mothers and fathers and the inheritance patterns in families with MAT vs. PAT transmission of the disease. In the total sample of 130 families we identified 39 families where the disease was transmitted from the paternal side (PAT families) and 35 families where the disease was transmitted from the maternal side (MAT families). Counting PAT and MAT transmissions in these unilineal families we found nearly equal numbers for both transmission types under a narrow (BP: bipolar disorder, schizoaffective-bipolar type disorder) and a broad definition (AFF: BP, recurrent unipolar depression) of the phenotype. The MRs for narrow and broad phenotypes were not significantly different in any type of PAT relative in PAT families vs. MAT relatives in MAT families. However, in PAT families there were two times more affected females than males with both disease models, while in MAT families there was no MR difference by relatives' sex. The transmission of BP was compatible with the Mendelian major gene model in PAT families and with the multifactorial model in MAT families. Extension of the relatives' phenotype led to borderline non-Mendelian major effects in PAT families and reproduced the multifactorial model in MAT families.

Patterns of parental transmission and familial aggregation models in bipolar affective disorder

Two recent studies [McMahon et al., 1995: Am J Hum Genet 56:1277–1286; Gershon et al., 1996: Am J Med Genet (Neuropsychiatr Genet) 67:202–207] reported an excess of maternal transmission in bipolar affective disorder in multiply affected families. In a sample of 130 families ascertained through a bipolar proband without regard to psychiatric family history we analysed the frequency of maternal (MAT) and paternal (PAT) transmissions, the morbid risk (MR) in relatives of transmitting mothers and fathers and the inheritance patterns in families with MAT vs. PAT transmission of the disease. In the total sample of 130 families we identified 39 families where the disease was transmitted from the paternal side (PAT families) and 35 families where the disease was transmitted from the maternal side (MAT families). Counting PAT and MAT transmissions in these unilineal families we found nearly equal numbers for both transmission types under a narrow (BP: bipolar disorder, schizoaffective-bipolar type disorder) and a broad definition (AFF: BP, recurrent unipolar depression) of the phenotype. The MRs for narrow and broad phenotypes were not significantly different in any type of PAT relative in PAT families vs. MAT relatives in MAT families. However, in PAT families there were two times more affected females than males with both disease models, while in MAT families there was no MR difference by relatives' sex. The transmission of BP was compatible with the Mendelian major gene model in PAT families and with the multifactorial model in MAT families. Extension of the relatives' phenotype led to borderline non-Mendelian major effects in PAT families and reproduced the multifactorial model in MAT families. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:397–404, 1998. © 1998 Wiley-Liss, Inc.

Segregation analysis of human red blood cell thiopurine methyltransferase activity

Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine (6-MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6-MP and other thiopurine drugs. Variation of TPMT activity in the red blood cell (RBC) has been found to reflect activity differences in less accessible tissues. Previously reported qualitative analyses of inheritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present study we completed complex segregation analyses of RBC TPMT activity of 213 individuals in 49 families that were randomly ascertained through children in the Rochester, MN, public school system. We found clear evidence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gene with frequency of 0.94 for the allele conferring high enzyme activity. The genotype distributions of individuals who were homozygous for the low activity allele, heterozygous, and homozygous for the high activity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respectively, of the individuals in the sample. This major locus accounted for 66% of the total variance in untransformed RBC TPMT activity. Although there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect additional major locus or polygenic inheritance effects on the residual variance.

Power of segregation analysis for detection of major gene effects on quantitative traits.

The power to detect major gene effects by rejection of the "no major gene" null hypothesis against a mixed model alternative was determined in random samples of nuclear families over a variety of conditions. Benchmarks have been developed using a varying number of families whose structure includes both parents and three children. Phenotypes were simulated assuming a Mendelian major gene under either recessive or dominant inheritance, with 0-30% residual polygenic heritability. Three trait prevalences--5, 10, and 20%--were considered in combination with increasing displacement between homozygous means, spanning a range of 14 to 36% of the phenotypic variance attributable to the major gene effect. All other assumptions of the traditional mixed model were adopted in the generating models. Segregation analysis was carried out on the simulated data sets and the proportion of samples out of 200 replications in which the null hypothesis q = 0 was rejected is reported as the power. Thus, failure to detect a major gene effect in this context is solely due to sampling variation, since no other perturbations were introduced. In general, there appears to be greater power to detect dominant major gene effects as opposed to recessive ones using otherwise comparable parameter values, and the effect of varying sibship size under dominant models appears to be greater as well. The use of joint vs. conditional likelihood calculations also was evaluated: substantial drops in power were observed when using conditional likelihoods under recessive inheritance, while the differences in power appeared to be nominal under dominant inheritance. The results of this investigation are offered as a guide to assist in the design of family studies whose aim is to detect major gene effects.

Two-locus and bivariate segregation analysis of HDL-C and apo AI.

Two-locus and bivariate segregation analyses of HDL-C and apo AI were carried out using the GAW8 Berkeley data set. For HDL-C, results are ambiguous. Both the mixed environmental model and the mixed Mendelian model fit the data equally well. For apo AI, however, univariate one-locus segregation analysis suggests a Mendelian major gene controlling its levels. Moreover, two-locus analysis suggests a second major gene is involved. Bivariate segregation analysis indicates these data cannot resolve the question as to whether a single Mendelian major gene with pleiotropic effects controls levels of both HDL-C and apo AI in humans.

Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity.

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2% of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50% of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model.(ABSTRACT TRUNCATED AT 250 WORDS)

Segregation and linkage analyses of bipolar and major depressive illnesses in multigenerational pedigrees

Data were collected on six large multigenerational pedigrees, four ascertained through a proband with major depression and two ascertained through a proband with a bipolar form of illness. Diagnoses were made using the SADS-L structured interview and Research Diagnostic Criteria (RDC). Complex segregation analyses were conducted on the bipolar and the major depression pedigree sets using a model allowing for both major locus and polygenic inheritance; in these analyses a variety of diagnostic schemes and assumptions concerning the lifetime population prevalence were examined. Linkage analyses on standard markers were conducted using parameters for transmission of susceptibility to illness derived from the segregation analyses. Results of the segregation analyses were quite sensitive to the diagnostic and prevalence assumptions. In the pedigrees ascertained through probands with a bipolar form of illness, we were unable to discriminate between major gene and polygenic inheritance. The data were compatible with Mendelian major gene transmission of susceptibility to illness when bipolar and schizoaffective manic diagnoses were considered as affected and the lifetime population prevalence was between 0.04 and 0.06. Outside this narrow prevalence range, or when additional diagnoses, such as major depression or hypomania, were included as expressions of liability to disease, major gene transmission of susceptibility to disease could be rejected. Similarly, in the pedigrees ascertained through probands with major depression, it was not generally possible to discriminate between major gene and polygenic transmission of susceptibility to illness. For a diagnostic scheme including only major depression as a manifestation of susceptibility to illness, there was a narrow range of lifetime population prevalence values (female prevalence ranging from 0.20 to 0.25, male prevalence set to 1/2 female prevalence) which yielded results compatible with major gene transmission. Linkage analyses for all markers yielded negative or inconclusive results. In one bipolar pedigree a lod score of 1.65 was found with a marker in chromosome 1 recommending further studies of this chromosome.