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PubMed1998

Familial correlation of dietary intakes among postmenopausal women.

A positive family history is a risk factor for many chronic diseases, including most cancers, coronary heart disease, and diabetes. Since diet is also associated with most chronic diseases, one possible explanation for non-Mendelian familial clustering is shared eating habits. Food frequency data were obtained on 3,515 sisters in the Iowa Women's Health Study, a prospective cohort of postmenopausal women. Intraclass correlations between sisters were computed on a range of energy-adjusted nutrients to determine whether dietary intakes were more similar among siblings than among unrelated individuals. Two methods were used to calculate correlations: analysis of variance modeling and weighted sibling correlations. F-tests and randomization tests were used to determine statistical significance. The intraclass correlations for all of the nutrients examined were statistically significantly greater than the hypothesized value of zero (P < 0.05). Representative correlations include dietary fiber (0.15), animal fat (0.12), vegetable fat (0.13), calcium (0.14), iron (0.04), cholesterol (0.08), sodium (0.10), vitamin D (0.16), and total energy intake (0.11). When corrected for measurement error, the magnitude of these correlations increased, on average 62%. Although modest in magnitude, these correlations may be high enough to influence familial clustering of complex diseases that are attributed, in part, to diet.

Aged↗

PubMed2005

Haplotype sharing transmission/disequilibrium tests that allow for genotyping errors.

The present study introduces new Haplotype Sharing Transmission/Disequilibrium Tests (HS-TDTs) that allow for random genotyping errors. We evaluate the type I error rate and power of the new proposed tests under a variety of scenarios and perform a power comparison among the proposed tests, the HS-TDT and the single-marker TDT. The results indicate that the HS-TDT shows a significant increase in type I error when applied to data in which either Mendelian inconsistent trios are removed or Mendelian inconsistent markers are treated as missing genotypes, and the magnitude of the type I error increases both with an increase in sample size and with an increase in genotyping error rate. The results also show that a simple strategy, that is, merging each rare haplotype to a most similar common haplotype, can control the type I error inflation for a wide range of genotyping error rates, and after merging rare haplotypes, the power of the test is very similar to that without merging the rare haplotypes. Therefore, we conclude that a simple strategy may make the HS-TDT robust to genotyping errors. Our simulation results also show that this strategy may also be applicable to other haplotype-based TDTs.

Algorithms↗

PubMed1990

Characterization of genomic polymorphism of an activation-associated antigen, Blast-1.

Blast-1 is a human activation-associated glycoprotein expressed on the surface of mononuclear cells, and a possible genetic marker for the manifestation of rheumatoid arthritis. In the present study, genomic polymorphism of the Blast-1 gene was analyzed using 100 healthy subjects. Restriction fragment length polymorphism (RFLP) of the Blast-1 gene was recognized only by Bam HI digestion among 46 restriction enzymes tested. The sizes of polymorphic fragments were 2.4 kilobase (kb) on the L band, and 1.9 kb on the S band. A family study demonstrated that the two alleles of the Blast-1 gene were inherited in a co-dominant Mendelian fashion. The genotype frequencies of homozygosity for the L and S bands were 47% and 42%, respectively, while the frequency of heterozygosity was 11%. The allele frequencies of the L and S bands were 0.68 and 0.32, respectively. The distribution of the Blast-1 genotypes in the present study was concordant with Hardy-Weinberg equilibrium (p greater than 0.7), which indicates that the frequency of the Blast-1 gene in the population is derived from random mating in preceding generations. The results of the present study may provide useful information in disease associations with the Blast-1 gene.

Antigens, CD↗

PubMed1985

DNA-mediated genetic transformation of mouse embryos and bone marrow--a review.

In recent years, new gene transfer systems have been developed which allow molecularly cloned genetic material to be introduced into whole organisms. These systems include the microinjection of DNA into mammalian embryos, transfection of DNA into mouse bone marrow cells, and the infection of early embryos with retroviruses. Exogenous DNA appears to integrate randomly into the host genome. The production of transgenic mice by injection of DNA into mouse embryos has rapidly gained importance as an experimental tool for the study of gene regulation during development. Through this technique, recombinant molecules of any type can be introduced into one-celled embryos, and thus can be used to study development from its earliest stages. DNA sequences have been shown to integrate and transmit through the germ line to subsequent generations as mendelian traits. Transgenic mice carrying various gene constructs have been successfully exploited for the elucidation of factors which determine tissue specificity of gene expression as well as the level of gene control. Phenotypic changes related to expression of foreign genes have also been observed. This experimental approach thus promises to rapidly solve many of the heretofore most challenging problems in developmental genetics. Insertion of foreign genes has also made possible the creation of insertional mutants which manifest themselves most frequently as recessives. Such mutations can be readily studied at the molecular level by using the transferred material as a probe for recovery of the affected host sequence from genomic libraries. Many of these same problems have been addressed by introducing retroviral DNA into mouse embryos. Here, the sequences used for transfer have been limited to retroviral genes, but nonetheless these experiments have been profitably exploited for studies both of gene regulation and mutagenesis. Gene transfer systems are being developed allowing the experimenter to transfer DNA into bone marrow cells of mice, after which the recipient cells can be reintroduced into lethally irradiated histocompatible animals. This system has the advantage that selection can be applied during the gene transfer process such that the expression of the foreign material is assured. In addition, these experiments have created a model system for production of animals carrying a subpopulation of cells which is highly resistant to a toxic agent. This system has the potential for therapeutic application to man.

Animals↗

PubMed2005

Statistical tools for linkage analysis and genetic association studies.

Genetic mapping by linkage analysis has been an invaluable tool in the positional strategy to identify the molecular basis of many rare Mendelian disorders. With the attention of the scientific and medical community shifting towards the analysis of more common, complex traits, it has become necessary to develop new approaches that take into account the complexity of the genetic basis of these disorders and their possible interaction with other, nongenetic factors. Linkage disequilibrium studies are now becoming increasingly popular thanks to the advent of genotyping platforms that allow genome-wide searching for association between hundreds of thousands of random polymorphisms and disease phenotypes in large samples of unrelated individuals. Moreover, the definition of the disease phenotype itself is being reconsidered to include quantitative traits that may better define the underlying biologic mechanisms for many pathologic conditions. This article will review classic and new approaches to genetic mapping by linkage and association analysis and discuss the directions this field is likely to take in the near future.

Alleles↗

PubMed1993

Influence of genotype-dependent effects of covariates on the outcome of segregation analysis of the body mass index.

Several recent studies of the body mass index (BMI) have provided support for a recessive major gene influencing heaviness in humans. Segregation analysis of the BMI was carried out recently in a series of randomly sampled French-Canadian families to determine whether we could replicate the major gene finding by using a residual phenotype adjusted for the effects of age and sex. The best model included a recessive major effect for high BMI values with residual familial resemblance; however, Mendelian transmission could not be confirmed, and the no-transmission hypothesis (where all the tau's are constrained to be equal) was not rejected. Considering that the BMI is a complex phenotype affected by many factors and that there are known variations in body composition during growth and aging, we undertook a reanalysis of the data, using a model that allowed the estimation of genotype-specific age and gender effects. New tests on the transmission parameters satisfy the criteria for interfering Mendelian segregation. The results suggest that individuals with the "high" recessive genotype show the greatest degree of heaviness at birth, with a subsequent trend toward lower values throughout life, while individuals with the dominant "normal" genotypes show no appreciable trends with age. In addition, the "high" genotype appears to confer a greater degree of heaviness in females as compared with males. These results, along with other observations from the data, suggest that, while a recessive single gene influence may be discernible, the phenotypic expression of the BMI is likely to be complicated by genotype x environment interactions and, possibly, by the action of other loci. Further, the data also are consistent with the hypothesis that modifying factors may include the adoption of a more prudent life-style by individuals genetically predisposed to heaviness and a secular increase in the incidence, prevalence, and potency of environmentally based triggers leading to a higher penetrance of the "heavy" genotype in the young.

Adolescent↗

PubMed1996

[Pedigree investigation of familial non-insulin dependent diabetes mellitus].

UNLABELLED: To discuss the inheritant mode of familial NIDDM. METHODS: According to WHO criteria of DM, 100 NIDDM Probands with family history of DM were diagnosed and 100 persons were chosen at random for controls. The survey of DM was performed in both groups, including FBG, HbAlc, FINS. Some members had insulin release test. RESULTS: The prevalance rates of DM in familial DM group were 26 times of the control group (34.3% and 1.3%). The prevalance rate of DM among first-degree relation was 18 times higher than that in general population (28.3% and 1.5%). The rate of diabetes in the siblings and in the off-springs was 44.4% and 9.7% respectively. The pedigree analyses showed that 83.9% affected families had one diabetic parent, one half siblings had DM, and there was a successive transmission of DM through at least three generations in sixteen large families. Besides, the incidence of DM was much higher in females than in males (40% and 28%). Among affected parents, diabetlic mothers were much more than diabetic fathers (50.8% and 27.6% P < 0.01). CONCLUSION: Familial NIDDM had a familial aggregation. It was inherited in the manner of Mendelian autosomal dominant inheritance. The difference between the rate in DM mothers and fathers was probably due to unequal prevalance rate in females and males.

Adult↗

PubMed2025

Whole-genome Sequence Analysis Revealed Novel Subjective Cognitive Decline-associated Genes in 10,763 Chinese.

Subjective cognitive decline (SCD) is widely regarded as a potential preclinical stage of Alzheimer's disease (AD), yet its genetic basis remains poorly understood. To address this gap, we investigated genetic biomarkers associated with SCD using whole-genome sequencing (WGS) in 10,763 Chinese participants from the Healthy Zhejiang One Million People Cohort (HOPE Cohort). The discovery stage included 9284 samples, with 1479 samples used for validation. Using a two-stage design, we systematically investigated both common and rare variants associated with SCD. In rare variant analyses, we identified and replicated an association between the upstream region of SEPHS2 and SCD. SEPHS2 is involved in selenophosphate synthesis, and a Mendelian randomization analysis reveals that its expression levels in both blood and brain cerebellum are associated with AD. Additionally, we identified CLVS2, which encodes a protein primarily expressed in neuronal cells, as a potential regulator for SCD based on missense rare variants. Multi-omics evidence suggests that both SEPHS2 and CLVS2 may play roles in neurodegenerative diseases. For common variants, we validated 8 known loci related to cognitive decline, 3 of which originated from the only existing SCD genetic study conducted under a migraine background. Overall, our WGS-based study fills the gap in SCD research by providing vital genetic evidence from an East Asian population and offers insights into the pathogenic mechanisms of SCD.

Aged↗

PubMed1993

Variance components for statistical genetics: applications in medical research to characteristics related to human diseases and health.

RA Fisher introduced variance components in 1918. He synthesized Mendelian inheritance with Darwin's theory of evolution by showing that the genetic variance of a continuous trait could be decomposed into additive and non-additive components. The model can be extended to include environmental factors, interactions, covariation, and non-random mating. Identifiability depends critically on design. Methods of analysis include modelling the mean squares from a fixed effects analysis of variance, and covariance structure modelling, which can be extended to multivariate traits and has been used to study ordinal traits by reference to postulated, unmeasured, latent 'liabilities'. These methods operate on dependent observations within independent groups of the same size and structure, and therefore require balanced designs ('regular' pedigrees). A multivariate normal model handles data in its generic form, utilizes data efficiently from all members of pedigrees of unequal size or varying structure, accommodates individuals missing at random, and allows flexible modelling with tests of distributional assumptions and fit. Most analytical methods use least squares or maximum likelihood under normal theory. Robust methods, scale transformation, ascertainment, path diagrams and correlational path models (popular in behavioural genetics through addressing nonrandom mating and social interactions), 'heritability', and the contribution and limitations of statistical modelling to the 'nature-nurture' debate, are discussed.

Genetic Diseases, Inborn↗

PubMed2004

Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies.

The calpain-10 gene (CAPN10) on chromosome 2q37.3 was the first candidate gene for type 2 diabetes (T2D) identified through a genomewide screen and positional cloning. One polymorphism (UCSNP-43: G-->A) and a specific haplotype combination defined by three polymorphisms (UCSNP-43, -19, and -63) were linked to an increased risk of T2D in several populations. To quantitatively assess the collective evidence for the effects of CAPN10 on risk of T2D, we conducted a meta-analysis of both population-based and family-based association studies. We retrieved data from the MEDLINE, PubMed, and Online Mendelian Inheritance in Man databases, as well as from other relevant reports and abstracts published up to July 2003. From a total of 26 studies with primary data (21 population-based studies: 5,013 cases and 5,876 controls; 5 family-based studies: 487 parent-offspring trios), we developed a summary database that contains variables of study design, study population/ethnicity, specific polymorphisms and haplotype combinations in CAPN10, and diabetes-related metabolic phenotypes. For population-based studies, we used both fixed-effects and random-effects models to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) for the associations of CAPN10 genotypes with the risk of T2D. We also calculated weighted mean differences for the associations between CAPN10 and diabetes-related quantitative traits. Under either an additive or a dominant effect model, we found no statistically significant relation between CAPN10 genotypes in the UCSNP-43 locus and T2D risk. However, under a recessive model, individuals homozygous for the common G allele had a statistically significant 19% higher risk of T2D than carriers of the A allele (OR 1.19; 95% CI 1.07-1.33). The association between the 112/121 haplotype combination and T2D risk appeared to be overestimated by several initial small studies with positive findings (OR 1.38; 95% CI 1.04-1.84). After we removed these initial studies, this association became nonsignificant (OR 1.11; 95% CI 0.91-1.35). Moreover, we found no evidence for the associations between the UCSNP-43 G/G genotype and the 112/121 haplotype combination and metabolic phenotypes. Our meta-analysis of family-based studies showed only an overtransmission of the rare allele C in UCSNP-44 from heterozygous parents to their affected offspring with T2D. Our analysis indicates that inadequate statistical power, racial/ethnic differences in frequencies of alleles, haplotypes and haplotype combinations, potential gene-gene or gene-environment interactions, publication bias, and multiple hypothesis testing may contribute to the significant heterogeneity in previous studies of CAPN10 and T2D. Our findings also suggest that both large-scale, well-designed association studies and functional studies are warranted to either reliably confirm or conclusively refute the initial hypothesis regarding the role of CAPN10 in T2D risk.

Alleles↗

PubMed1999

Production of fertile unreduced sperm by hybrid males of the Rutilus alburnoides complex (Teleostei, cyprinidae). An alternative route to genome tetraploidization in unisexuals.

The hybrid minnow Rutilus alburnoides comprises diploid and polyploid females and males. Previous studies revealed that diploid and triploid females exhibit altered oogenesis that does not involve random segregation and recombination of the genomes of the two ancestors, constituting unisexual lineages. In the present study, we investigated the reproductive mode of hybrid males from the Tejo basin, using experimental crosses and flow cytometric analysis of blood and sperm. The results suggest that diploid hybrids produced fertile unreduced sperm, transmitting their hybrid genome intact to offspring. Triploid hybrids also produced unreduced sperm, but it was not possible to obtain data concerning their fertility. Finally, tetraploid hybrids produced fertile diploid sperm, which exhibited Mendelian segregation. Tetraploid R. alburnoides may reestablish biparental reproduction, as individuals of both sexes with the appropriate constitution for normal meiosis (two haploid genomes from each parental species) are likely to occur in natural populations. Tetraploids probably have arisen from syngamy of diploid eggs and diploid sperm produced by diploid hybrid males. Diploid hybrid males may therefore play a significant role in the dynamics of the complex, starting the evolutionary process that may ultimately lead to a new sexually reproducing species.

Animals↗

PubMed2026

Genome-wide association studies of plant traits and functional analysis of leaf development-related genes in citrus.

Labor-saving and high-light-efficiency tree architecture is a key breeding objective for woody fruit trees like citrus. However, population genetics information on these traits remains limited. In this study, tree architecture, thorn, and leaf traits were evaluated in 353 F2 progeny derived from a cross between Clementine mandarin and precocious trifoliate orange-an early-flowering variety. A random subset of 300 offspring was sequenced for a genome-wide association study (GWAS), which detected 10 216 significantly associated SNPs and defined several major quantitative trait loci (QTLs) for the target traits. Subsequent bulked segregant analysis (BSA) and GWAS on individuals with extreme compound leaf phenotypes mapped the causal gene(s) to a 0.8 Mb region (22.15-22.95 Mb) on chromosome 4. Genetic analysis across multiple hybrid combinations confirmed that the compound leaf trait in trifoliate orange is dominantly inherited and follows Mendelian segregation. Transcriptome profiling of parental leaves at different developmental stages identified a KNOX gene, CiKNAT6, as a candidate. Further validation using CAPS markers and Hi-Tom sequencing demonstrated tight linkage between an InDel polymorphism in CiKNAT6 and leaf shape across diverse citrus species and the F2 population, with co-segregation observed for the compound leaf trait. Due to alternative splicing producing seven splice variants, the CiKNAT6 DNA sequence was selected for genetic transformation experiments. Functional analysis revealed that the Clementine mandarin allele of CiKNAT6 is non-functional owing to an InDel, whereas ectopic expression of the trifoliate orange allele in tobacco and lemon induced leaf curling and reduced leaf size. CRISPR-Cas9 knockout of CiKNAT6 in trifoliate orange resulted in increased leaf area. These findings provide valuable genetic resources and insights for future studies on tree architecture and leaf morphology.

Plant Leaves↗

PubMed2003

Precise mapping of a locus affecting grain protein content in durum wheat.

Grain protein content (GPC) is an important factor in pasta and breadmaking quality, and in human nutrition. It is also an important trait for wheat growers because premium prices are frequently paid for wheat with high GPC. A promising source for alleles to increase GPC was detected on chromosome 6B of Triticum turgidum var. dicoccoides accession FA-15-3 (DIC). Two previous quantitative trait locus (QTL) studies found that the positive effect of DIC-6B was associated to a single locus located between the centromere and the Nor-B2 locus on the short arm of chromosome 6B. Microsatellite markers Xgwm508 and Xgwm193 flanking the QTL region were used in this study to develop 20 new homozygous recombinant substitution lines (RSLs) with crossovers between these markers. These 20 RSLs, plus nine RSLs developed in previous studies were characterized with four new RFLP markers located within this chromosome segment. Grain protein content was determined in three field experiments organized as randomized complete block designs with ten replications each. The QTL peaks for protein content were located in the central region of a 2.7-cM interval between RFLP markers Xcdo365 and Xucw67 in the three experiments. Statistical analyses showed that almost all lines could be classified unequivocally within low- and high- protein groups, facilitating the mapping of this trait as a single Mendelian locus designated Gpc-6B1. The Gpc-6B1 locus was mapped 1.5-cM proximal to Xcdo365 and 1.2-cM distal to Xucw67. These new markers can be used to reduce the size of the DIC chromosome segment selected in marker-assisted selection programs. Markers Nor-B2 and Xucw66 flanking the previous two markers can be used to select against the DIC segment and reduce the linkage drag during the transfer of Gpc-6B1 into commercial bread and pasta wheat varieties. The precise mapping of the high GPC gene, the high frequency of recombinants recovered in the targeted region, and the recent development of a tetraploid BAC library including the Gpc-6B1 DIC allele are the first steps towards the map-based cloning of this gene.

Alleles↗

PubMed2005

Trans events associated with crossovers are revealed in the absence of mismatch repair genes in Saccharomyces cerevisiae.

Genetic analysis of recombination in Saccharomyces cerevisiae has revealed products with structures not predicted by the double-strand break repair model of meiotic recombination. A particular type of recombinant containing trans heteroduplex DNA has been observed at two loci. Trans events were originally identified only in tetrads in which the non-Mendelian segregations were not associated with a crossover. Because of this, these events were proposed to have arisen from the unwinding of double Holliday junctions. Previous studies used palindromes, refractory to mismatch repair, as genetic markers whereas we have used a complementary approach of deleting mismatch repair proteins to identify heteroduplex DNA. We found that the markers occurred in trans and were associated with crossovers. In both mlh1Delta and msh2Delta strains, the frequency of trans events associated with a crossover exceeded that predicted from the random association of crossovers with noncrossover trans events. We propose two different models to account for trans events associated with crossovers and discuss the relevance to wild-type DSB repair.

Alcohol Oxidoreductases↗

PubMed2004

Comparative study of multipoint methods for genotype error detection.

Several programs are currently available for the detection of genotyping error that may or may not be Mendelianly inconsistent. However, no systematic study exists that evaluates their performance under varying pedigree structures and sizes, marker spacing, and allele frequencies. Our simulation study compares four multipoint methods: Merlin, Mendel4, SimWalk2, and Sibmed. We look at empirical thresholds, power, and false-positive rates on 7 small pedigree structures that included sibships with and without genotyped parents, and a three-generation pedigree, using 11 microsatellite markers with 3 different map spacings. Simulated data includes 5,000 replicates of each pedigree structure and marker map, with random genotyping errors in about 4% of the middle marker's genotypes. We found that the default thresholds used by these programs provide low power (47-72%). Power is improved more by adding genotyped siblings than by using more closely spaced markers. Some mistyping methods are sensitive to the frequencies of the observed alleles. Siblings of mistyped individuals have elevated false-positive rates, as do markers close to the mistyped marker. We conclude that thresholds should be decided based on the pedigree and marker data and that greater focus should be placed on modeling genotyping error when computing likelihoods, rather than on detecting and eliminating genotyping errors.

Alleles↗

PubMed2026

Shared genetic architecture of smoking dependence and Crohn's disease: A cross-trait analysis of GWAS summary statistics.

INTRODUCTION: Smoking dependence (SD) and Crohn's disease (CD) are epidemiologically associated, but whether this relationship reflects shared genetic susceptibility remains unclear. METHODS: We conducted a cross-trait genetic analysis of SD and CD using publicly available genome-wide association study (GWAS) summary statistics from European-ancestry populations. Genome-wide genetic correlation was estimated using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Pleiotropic variants were identified using PLACO and mapped to genomic loci using FUMA. Regional signal sharing was assessed by Bayesian colocalization. Functional analyses included stratified LDSC, Multi-marker Analysis of GenoMic Annotation (MAGMA), GTEx tissue analysis, and Metascape. Expression-linked candidate genes were prioritized using expression quantitative trait locus (eQTL)-based summary-data-based Mendelian randomization (SMR) with heterogeneity in dependent instruments (HEIDI) testing. Genetically informed spatial mapping of cells for complex traits (gsMap) was used for spatial mapping. RESULTS: SD and CD showed positive genetic correlation by LDSC (rg=0.2090, p=0.0008) and HDL (rg=0.3817, p=0.00106). PLACO identified 81 genome-wide significant pleiotropic SNPs, which were mapped by FUMA to three loci at 1p31.3, 5p13.1, and 12q12, represented by rs11209031, rs1395152, and rs17467116, respectively. MAGMA identified 22 FDR-significant genes, four of which remained Bonferroni significant: LRRK2, TNFRSF6B, ZGPAT, and RP4-583P15.15. Cross-trait tissue analysis showed significant enrichment of the shared genetic signal in whole blood and small intestine, while gene-set analysis highlighted inflammatory response (pbon=1.86×10-5) and T-helper 17 cell differentiation (pbon=7.37×10-4). SMR/HEIDI analysis further prioritized RPS6KB1 as a shared expression-linked candidate. Spatial mapping revealed a prominent signal in the embryonic gastrointestinal tract and gene-specific regional patterns involving LRRK2 and SLC2A13 in the adult mouse brain. CONCLUSIONS: SD and CD showed measurable shared genetic susceptibility, with convergent evidence from pleiotropic loci, immune-inflammatory pathway enrichment, tissue-level associations, and spatial transcriptomic mapping.

Crohn's disease↗

PubMed1997

Semiparametric estimation of major gene and family-specific random effects for age of onset.

Analysis of familial diseases with variable age of onset is a common problem in human genetics. Most existing methods make some parametric distributional assumption on age of onset, and few methods have been designed with the goal of testing the hypothesis of a Mendelian gene against other hypotheses of familial dependence. We introduce the Cox model with major genetic and random familial effects to model age-of-onset dependence patterns among family members and to incorporate family heterogeneity. This model allows testing for and estimating major gene effects in the presence of residual correlations. Generalized maximum likelihood estimation using a Monte Carlo EM algorithm is used for parameter estimation. The methods are illustrated by a simulated data set and a data set from a case-control family study of breast cancer.

Adult↗

PubMed1985

The heterogeneity problem. I: Separating genetic from environmental forms of the same disease.

The purposes of this work were 1) to reparameterize the likelihood used in segregation analysis in a way particularly suited to detecting heterogeneity (the result of the analysis is a parameter giving the proportion of families with the genetic form of the disease in the dataset) and 2) to test how well this reparameterization works using simulation. We assume that a dataset contains nuclear family data, with some of the families having a form of the disease that is environmentally caused and the others with a genetic form of the disease. In this study, we considered the case where the genetic form is a simple recessive and the environmental form a random model. The underlying parameters were the gene frequency, q, and the frequency of sporadics, R. We reparameterized the likelihood in terms of alpha, the percentage of genetic families in the dataset, which we attempt to estimate. We contrast the estimates of alpha with the population heterogeneity as reflected in the estimates of q and R. For the simulation, nuclear families are generated. Genetic families were simulated with a mendelian recessive pattern and environmental families according to a simple random model. Over a wide range of generating parameters, estimates of alpha were good, differing from the "true" values by only a few percent. Estimates of q and R, on the other hand, ranged from fair to poor. Our results indicate that the amount of heterogeneity in a dataset can be accurately estimated using segregation analysis, even when estimates of the gene frequency and penetrance among sporadics are unreliable.

Environment↗