Complex Segregation Analysis Research Articles

Complex segregation analysis of nasopharyngeal carcinoma in Guangdong, China: evidence for a multifactorial mode of inheritance (complex segregation analysis of NPC in China).

The striking geographical and ethnic distribution of nasopharyngeal carcinoma (NPC) suggests the involvement of genetic and environmental factors in NPC development. The purpose of this study is to investigate the fit of single gene, polygenic and multifactorial models to the observed pattern of transmission of NPC in a hospital-based family history study conducted by the Cancer Center of Sun Yat-Sen University (CCSYU) in Guangzhou, China. Complex segregation analysis of a total of 1903 Cantonese pedigrees ascertained at CCSYU was conducted using a unified mixed model after the pedigrees were partitioned into 3737 nuclear families. The mixed model assumes that a phenotype is influenced by the additive and independent effect of a major gene, together with multifactorial components (genetic and environmental) and a random environmental effect. The current results do not provide evidence for a major gene and the observed data are best explained by a multifactorial mode of inheritance for NPC.

Characteristics of genetic epidemiology and genetic models for vitiligo

Background Vitiligo occurs with a frequency of 0.1% to 2% in various populations and is classified into several subtypes by its clinical presentation. Although genetic factors are thought to be involved in the cause of vitiligo, the genetic models for different phenotypes of vitiligo are unknown. Objective Our purpose was to explore potential genetic models for different phenotypes of vitiligo and analyze genetic epidemiologic characteristics of vitiligo in a Chinese population. Methods Information from 2247 patients and members in their families was collected using a uniform questionnaire. Patients' clinical characteristics and their family history were analyzed using software. A complex segregation analysis was conducted to propose potential genetic models for vitiligo. Results Different subtypes of vitiligo had different ages of disease onset. In relatives of patients with vitiligo, the risk of developing vitiligo increased with increasing relatedness to the patients with vitiligo. A polygenic additive model was the best model for focal vitiligo, vitiligo vulgaris, acrofacial vitiligo, and segmental vitiligo with approximately 50% heritability in each. For universal vitiligo, the best model was an environmental model. Conclusion This study indicated that different phenotypes of vitiligo had different pathogeneses and genetic backgrounds. Onset of vitiligo is possibly affected by both genetic backgrounds and common environmental factors.

The genetic epidemiology of alopecia areata in China.

Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease with genetic predisposition and an environmental trigger. There are few clinical data in Asians. To describe the genetic epidemiological features of AA patients in China and to determine the possible genetic model for AA. Data for 1032 patients with AA were obtained by questionnaire in the Institute of Dermatology of Anhui Medical University in China from 2001 to 2003. Complex segregation analysis and heritability analysis were performed using Falconer's method, EPI INFO 6.0 and SAGE-REGTL programs. In total, 1032 AA patients (male/female ratio 1.1 : 1) were enrolled, representing 0.94% of the total number of cases seen in our outpatient clinic during that time. The mean +/- SD age of onset was 28.98 +/- 13.43 years. The difference between the mean age of onset in males and females was not significant. Most patients (82.6%) experienced their first episode of AA within the first four decades of life. A positive family history of AA was obtained in 87 patients (8.4%). The prevalence of AA in first-, second- and third-degree relatives of the proband with AA was 1.6%, 0.19% and 0.03%, respectively. These figures were higher than those in controls. A greater severity and longer duration of AA were seen in the early onset group than in the late-onset group. The early onset group also had more affected first- and second-degree relatives. The heritability of AA in first-, second- and third-degree relatives was 47.16%, 42.53% and 22.29%, respectively. Based on the REGTL results, the best model was a polygenic additive model for AA. The effect of genetic factors is strong in AA, but environmental factors such as infection and psychological stress may still play an important role. Our findings on the genetics of AA are consistent with a polygenic additive mode of inheritance.

Hereditary Ataxia in the Jack Russell Terrier– Clinical and Genetic Investigations

Hereditary ataxia in the Jack Russell Terrier (JRT) is characterized by a gait disturbance with symmetric generalized ataxia and hypermetric and spastic movements. Histopathology shows a disease of the entire central nervous system, predominantly an axonopathy. In the present study, 35 clinically affected dogs were examined. Gait abnormalities began at 2–9 months of age. Generalized seizures occurred in 13 dogs in addition to the ataxia, and 7 dogs developed respiratory distress. Brain stem auditory‐evoked potentials (BAEPs) were abnormal in 4 of 8 examined dogs, in which only waves I and II were detected. Abnormal BAEPs suggest the possibility of hereditary ataxia in the JRT. Investigations regarding the mode of inheritance were performed by complex segregation analyses on 3 pedigrees with a total of 115 JRTs (27 clinically affected dogs and 88 unaffected littermates and ancestors). Different modes of inheritance were tested, including monogenic, mixed, and polygenic models, as well as a model with environmental effects only. Models with genetic effects explained the data significantly better than the environmental model. The monogenic model had to be rejected in this study because of an insufficient match of data when compared to that of the most general model. The polygenic and mixed major gene models explained the pedigree data best and therefore have to be regarded as possible hypotheses for the mode of inheritance of hereditary ataxia in the JRT. The polygenic model proved best suited to explain the segregation pattern in the JRT, because it had the fewest number of parameters.

Genetics of bone mineral density: evidence for a major pleiotropic effect from an intercontinental study.

BMD is a primary predictor of osteoporotic fracture, and its genetic determination is still unclear. This study showed that the correlation between BMD at different skeletal sites is caused by an underlying genetic structure of common genetic effects. In addition to possible shared (pleiotropic) genetic and environmental effects, each of the BMD variables may also be determined by site-specific genetic factors. BMD is a primary predictor of osteoporotic fracture and a key phenotype for the genetic study of osteoporosis. The interindividual variation in BMD measured at a given skeletal site is largely regulated by genetic factors. A strong phenotypic covariation exists for BMD at different skeletal sites. This study tests the hypothesis that the covariation is in fact caused by an underlying genetic structure of common genetic effects and that, in addition to possible shared (pleiotropic) genetic effects, each of the BMD variables may also be determined by site-specific genetic factors A bivariate complex segregation analysis as implemented in statistical package PAP was conducted to explore various models of pleiotropic genetic and environmental transmission in lumbar spine and femoral neck BMD, as well as in compact and spongious segments of hand phalanges. The BMD was obtained in three ethnically, culturally, and socially heterogeneous samples of white pedigrees, with 2549 individuals between 18 and 100 years of age, from Australia, Europe, and North America. The genetic correlation between BMD measures ranged between 0.50 +/- 0.09 and 0.79 +/- 0.04 in the three samples. In each sample, the model incorporated a major locus pleiotropic effect, and residual correlation was found to be the most parsimonious model. Estimated parameters from the model indicated a significant pleiotropic major gene effect on both lumbar spine and femoral neck BMD, with the existence of a significant residual correlation (0.51 +/- 0.07 to 0.66 +/- 0.04). These results suggest that the covariation in BMD at different skeletal sites, and between mostly compact versus mostly trabecular bone, was largely determined by common genetic factors that are pleiotropic or in close linkage and linkage disequilibirum, while at the same time, exhibiting considerable evidence of shared environmental effects. The results, for the first time, suggest that the possibility of pleiotropic genetic effect may be controlled by a major genetic locus. Identification of the major locus could open new opportunity to understanding the liability and pathogenic processes in which they are involved in the determination of fracture risk.

Familial segregation of venous thromboembolism

Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain. To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance. In a family-based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age-specific, non-gender- and gender-specific liability classes under Mendelian and non-Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non-Mendelian. Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first-degree relatives. The sporadic model was rejected in both non-gender- and gender-specific liability class analyses. Among the remaining gender-specific models, the unrestricted (non-Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes. A multifactorial non-Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.

Complex segregation analyses of bone mineral density in Chinese.

China has the largest population in the world; approximately 7% of the total population suffers from primary osteoporosis. Osteoporosis is mainly characterized by low bone mineral density (BMD). In the present study, familial correlation and segregation analyses for spine and hip BMDs have been undertaken for the first time in a Chinese sample composed of 401 nuclear families with a total of 1260 individuals. The results indicate a major gene of additive inheritance for hip BMD, whereas there is no evidence of a major gene influencing spine BMD. Significant familial residual effects are found for both traits, and heritability estimates (+/-SE) for spine and hip BMDs are 0.807(0.099) and 0.897(0.101), respectively. Sex and age differences in genotype-specific average BMD are also observed. This study provides the first evidence quantifying the high degree of genetic determination of BMD variation in the Chinese.

Hereditary ataxia in the Jack Russell Terrier--clinical and genetic investigations.

Hereditary ataxia in the Jack Russell Terrier (JRT) is characterized by a gait disturbance with symmetric generalized ataxia and hypermetric and spastic movements. Histopathology shows a disease of the entire central nervous system, predominantly an axonopathy. In the present study, 35 clinically affected dogs were examined. Gait abnormalities began at 2-9 months of age. Generalized seizures occurred in 13 dogs in addition to the ataxia, and 7 dogs developed respiratory distress. Brain stem auditory-evoked potentials (BAEPs) were abnormal in 4 of 8 examined dogs, in which only waves I and II were detected. Abnormal BAEPs suggest the possibility of hereditary ataxia in the JRT. Investigations regarding the mode of inheritance were performed by complex segregation analyses on 3 pedigrees with a total of 115 JRTs (27 clinically affected dogs and 88 unaffected littermates and ancestors). Different modes of inheritance were tested, including monogenic, mixed, and polygenic models, as well as a model with environmental effects only. Models with genetic effects explained the data significantly better than the environmental model. The monogenic model had to be rejected in this study because of an insufficient match of data when compared to that of the most general model. The polygenic and mixed major gene models explained the pedigree data best and therefore have to be regarded as possible hypotheses for the mode of inheritance of hereditary ataxia in the JRT. The polygenic model proved best suited to explain the segregation pattern in the JRT, because it had the fewest number of parameters.

Complex segregation and linkage analysis of familial gout in Taiwanese aborigines.

The prevalence of gout and hyperuricemia in Taiwanese aborigines is remarkably high. Although previous studies have failed to find evidence of a major gene responsible for gout, the disease is thought to involve genetic predisposition. We sought to determine whether genetic factors for familial gout exist among Taiwanese aborigines, and, if so, their chromosomal location. We first performed complex segregation analysis. The study sample comprised 945 relatives distributed in 64 pedigrees; among them, 261 affected members (including probands) were found. In all of the aboriginal probands with gout, the disease was diagnosed and confirmed by rheumatologists. Blood specimens were then collected from 127 individuals living in one community that was used in the segregation analysis (from 25 pedigrees, 36 nuclear families, and 112 full sibpairs), and sibpair linkage analysis and a combined transmission disequilibrium test (TDT) method were used to test the genetic components. In segregation analysis, after adjusting for sex and age, an autosomal-arbitrary major gene model was found to fit the data best, with disease allelic frequency of 0.31 and susceptibility of 0.92. In sibpair analysis, there was a clustering of many flanking markers showing significant linkage, including D1S498 (regression coefficient -0.52), D1S2635 (regression coefficient -0.47), and D1S196 (regression coefficient -0.51), in the 1q21 region of chromosome 1 (all P < 0.005). Results of the combined TDT showed that the marker D1S484 was significantly associated (had linkage) with allele 1 and was transmitted more frequently than other markers to the affected offspring (P < 0.005). Results of this study provide evidence of a genetic basis for familial gout in the aboriginal Taiwanese population and suggest that a susceptibility locus may be located in the 1q21 region of chromosome 1.

Evidence for a major gene influence on persistent developmental stuttering.

Stuttering is a complex developmental speech disorder of unknown etiology. There is a substantial aggregation of stuttering in families, suggesting a genetic component to the disorder. However, the exact mode of transmission is still unknown. An earlier study of 56 multigenerational pedigrees ascertained through single adult probands (38 males and 18 females) found that biological relatives of persistent developmental stutterers have an approximately 10-fold higher risk than in the general population; risk is higher for male relatives, and proband's sex does not affect recurrence and relative risks. In the present paper we conduct a complex segregation analysis of the same data, using the logistic regression model of the SAGE software. Based on the comparisons of model likelihoods, the Mendelian model was selected over all other nongenetic models and the general transmission model. This model was further refined into the most parsimonious model, which shows an autosomal dominant major gene effect influenced by two covariates: sex and affection status of parents. With this model applied to 47 informative multiplex pedigrees, a power calculation based on linkage simulation produced an average lod score of 6.8 for 10-cM density genome scan markers. These results give impetus for a genomewide linkage analysis of susceptibility to persistent developmental stuttering.

Inheritance of white head spotting in natural populations of South American water rat (Nectomys squamipes Rodentia: Sigmodontinae).

Specimens with white head spots are present at low frequency in the natural populations of South American water rat (Nectomys squamipes) and absent in the sibling species Nectomys rattus. We analyzed the pattern of inheritance of the phenotype using complex segregation analysis of pedigrees of a captive-bred population of N. squamipes. We found that the inheritance of the white head spot in this species can be described within the framework of the major gene recessive model with incomplete penetrance of genotypes.

Cancer aggregation and complex segregation analysis of families with female non-smoking lung cancer probands in Taiwan

Previous studies have found that having a first-degree blood relative with lung cancer was a possible predictor of lung cancer risk, but some studies have indicated that the association is non-significant or only significant for a subset of the studied population. To determine the familial aggregation and whether there is any evidence for a gene controlling the susceptibility to developing lung cancer in female non-smokers, multiple logistic regression methods for estimating covariate effects and maximum likelihood segregation analyses were performed using data from 216 female non-smoking lung cancer probands (2328 individuals) in a population-based case–control study. Having a family history of lung cancer was found to be a significant predictor of lung cancer for non-smoking females (Adjusted Odds Ratio (OR)=5.7, 95% Confidence Interval (CI)=1.9–16.9). Having a female relative with lung cancer (adjusted OR=14.4, 95% CI=2.7–75.5) was more strongly associated with the lung cancer risk than was having a male relative with lung cancer. This association was stronger for probands aged less than 60 years at onset (adjusted OR=11.2, 95% CI=2.2–56.9). All of the Mendelian models fitted the data significantly better than the sporadic (no major type) model or the environmental model (P<0.00l). The Mendelian codominant models provided the best fit of the data for the early onset probands and showed a stronger effect for a major susceptibility locus for non-smoking lung cancer probands. The results of this study provide evidence that a rare autosomal codominant gene may influence the risk lung cancer in non-smoker and is responsible for the familial aggregation observed in non-smoking lung cancer patients.

Substantial genetic effects involved in determination of circulating levels of calciotropic hormones in human pedigrees.

This paper reports the results of a series of univariate and bivariate statistical genetic analyses that were performed on a sample of nuclear and more complex pedigrees (N = 567 individuals) of an ethnically homogenous White population. Our major objectives were: (1) To quantitatively evaluate the extent and pattern of the putative genetic effects on plasma level variation and covariation of the intact parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D]; (2) To evaluate the extent of the possible genetic covariation between each of the two calciotropic hormones and two important bone mass traits, namely radiographic hands bone mineral density (BMD) and cortical index (CI). Variance component analysis, as implemented in the statistical package FISHER unambigously demonstrated that in addition to age, genetic factors contribute significantly to interindividual variation of both calciotropic hormones (37.5% for PTH and 53.3% for 25(OH)D). Complex segregation analysis strongly suggested the involvement of major gene effects into the determination of 25(OH)D levels, but was not clear cut with respect to PTH. Significant correlations between circulating levels of study hormones were found (-0.146, P < 0.05 in men and -0.194, P < 0.01 in women). However, no genetic correlation was revealed between PTH and 25(OH)D plasma concentrations. Bivariate analyses showed that familial cross correlations between PTH and BMD and CI measured at the bones of the hand were consistently statistically significant, suggesting moderate, but detectable pleiotropic genetic effects. The corresponding genetic correlations were -0.461 +/- 0.153 and -0.223 +/- 0.113, respectively. Circulating levels of 25(OH)D showed neither phenotypic nor genetic correlation with any of the BMD or CI variation.

Site and gender specificity of inheritance of bone mineral density.

Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability. Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis. We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < -2.5, Z-score < -2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck. Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3-19%, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61-67% and at the femoral neck was 44-67%. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < -2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck. These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.

Segregation analysis of phenotypic components of learning disabilities. II. Phonological decoding.

Dyslexia is a common, complex disorder, which is thought to have a genetic component. The study of the genetics of dyslexia is complicated by a lack of consensus on diagnostic criteria, and the probability of genetic heterogeneity-it is possible that deficits in different language processes are caused by different underlying genes. In order to address these difficulties, we study continuous phenotypes that are part of the psychometric test batteries often used to diagnose dyslexia. Prior to embarking on a linkage study, it is helpful to employ segregation analysis, both to identify phenotypes that may be amenable to mapping by linkage analysis, and to determine the best models to use for model based analyses. We study 409 people in 102 nuclear families, and employ (1) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) contributing to each phenotype, and (2) complex segregation analysis in order to identify the most parsimonious inheritance model. In this paper, we consider two measures of phonological decoding ability-word attack and phonemic decoding efficiency. We find evidence for one or two genes of at least modest effect contributing to phonemic decoding efficiency, and the best fitting model is a dominant major gene model with residual familial correlations. For word attack, we find evidence for one or two genes of at least modest effect, and the variation in the trait is best explained by a polygenic model.

Complex segregation analysis of 1,792 cleft lip and palate families in South America: 1967-1997.

Although several studies have demonstrated familial aggregation of nonsyndromic cleft lip with or without cleft palate (CL/P), its model of inheritance remains uncertain. We report the results of complex segregation analysis performed in South American families with a newborn affected with CL/P. Families of 1,792 consecutive newborns affected with CL/P and registered during the period 1967 to 1997 were studied. A model that did not include a major locus was the best-fitting model for CL/P families. This result is in agreement with previous studies which showed a significant association of several putative susceptibility loci and CL/P, indicating that the genes involved in CL/P are likely to have only a very modest impact on disease risk.

Inheritance of cleft palate in South America: evidence for a major locus recessive.

Determine the model of inheritance of non-syndromic cleft palate in humans. Complex segregation analysis performed in families of consecutive newborns affected with non-syndromic cleft palate. The Latin American Collaborative Study of Congenital Malformations (ECLAMC). Four hundred and seven consecutive newborns affected with non-syndromic cleft palate registered during the period 1967-97. Likelihood ratio test and Akaike information criterion (AIC) values. The single major locus recessive model provided a significantly better explanation of the data. It was the most parsimonious and had the smallest AIC value of the six models tested with approximately the same likelihood as the general model (chi2 = 2.44, p = 0.5). To have defined a genetic model for non-syndromic cleft palate and provided evidence for a single major locus inheritance suggests that genetic linkage studies could be implemented.

Analyses for the presence of a major gene affecting uterine capacity in unilaterally ovariectomized rabbits.

The presence of a major gene for uterine capacity (UC), ovulation rate (OR), number of implanted embryos (IE), embryo survival (ES), fetal survival (FS), and prenatal survival (PS) was investigated in a population of rabbits divergently selected for UC for 10 generations. Selection was performed on estimated breeding values for UC up to four parities. UC was estimated as litter size in the remaining overcrowded horn of unilaterally ovariectomized does. OR and IE were counted by means of laparoscopy. Bartlett's test, Fain's test, and a complex segregation analysis using Bayesian methods were used to test for the presence of a major gene. All three tests showed that the data appeared consistent with the presence of a major gene affecting UC and IE. The results of the complex segregation analysis suggested the presence of a major gene with large effect on IE and ES (a > 1sigma(p)), at high frequency (p = 0.70 and 0.68, respectively), and with a large contribution to the total variance (R(g) = 0.39 and 0.47, respectively); and the presence of a major gene with moderate effect on each of OR, FS, PS, and UC. The results suggest that the studied reproductive traits are determined genetically by at least one gene of large effect.

Major gene effects in systolic and diastolic blood pressure in families receiving a health examination in Taiwan.

Genetic factors play an important role in determining blood pressure values. Strong familial aggregation and estimated heritability values around 0.4-0.6 were reported in a white population. To investigate the genetic components and mode of inheritance of blood pressure in Taiwan. A cross-sectional family study based on an adult population undergoing a health examination. A total of 1313 adults and their spouses or first-degree relatives, or both, underwent a health examination in a tertiary university hospital from August 1998 to September 1999. Genetic analyses, including comingling analysis, familial correlation and complex segregation analysis, were used to detect the genetic components and the mode of inheritance of blood pressures. In both systolic and diastolic blood pressure, the comingling analyses demonstrated that a more than one-component distribution provided the best fit for the data. The familial correlation coefficients showed significant parent-offspring and sibling correlation. Complex segregation analyses showed major gene effects in controlling systolic and diastolic blood pressure. There were significant genetic components in blood pressure among Taiwanese. Further investigation of genomic loci for the control of blood pressure is indicated.

Segregation analysis of hepatocellular carcinoma in a moderately high-incidence area of East China.

To explore the mode of inheritance of hepatocellular carcinoma (HCC) in a moderately high-incidence area of East China. A pedigree survey was conducted in 210 families (3315 individuals) ascertained through 210 HCC probands in Haimen, Jiangsu Province. Simple segregation analysis was conducted using SEGRANB software. The probability of ascertainment (pi), segregation ratio (p), and the proportion of sporadic cases (x) were estimated. Complex segregation analysis was performed using the REGTL program of S.A.G.E. Models were fitted on the data of 3212 individuals that allowed for personal HBsAg status and variable age of onset in REGTL program. The estimate of segregation ratio was 0.191 by SEGRANB. The probability of ascertainment was 0.0266, and the proportion of sporadic cases was 0.465. The results of complex segregation analysis showed that Mendelian autosomal recessive inheritance of a major gene that influenced the age of onset distribution of HCC, provided the best fit to the data. In the best-fitting recessive model, the frequency of the disease allele was 0.11138. HBsAg seropositive status would significantly increase the risk of developing HCC. These results suggest that at least one major gene is involved in the genetic predisposition to develop HCC at an earlier age of onset. The seropositive HBsAg status can significantly increase the risk of developing HCC, which provides strong support for the interaction between genetic and environmental risk factors.