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PubMed1993

Two-trait-locus linkage analysis: a powerful strategy for mapping complex genetic traits.

Recent advances in molecular biology have provided geneticists with ever-increasing numbers of highly polymorphic genetic markers that have made possible linkage mapping of loci responsible for many human diseases. However, nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, we explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. We compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. We also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, we also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that we consider, we find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, we also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. We also discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models.

Chromosome Mapping↗

PubMed1991

Body measurements of crossbred calves sired by Simmental bulls divergently selected for progeny first-calf calving ease in relation to birth weight.

Simmental bulls (n = 27) were divergently selected on linear model first-calf calving ease expected progeny difference (CEPD) relative to birth weight expected progeny difference (BEPD) so that body measures of calves from sires whose progeny tended to be born either with more or less dystocia than expected from BEPD could be obtained. At birth, calf weight, head circumference, shoulder width, hip width, heart girth, cannon bone circumference and length, and body length were recorded for 204 calves. These measures had also been obtained from the Polled Hereford X Angus dams of the calves at their births. Sire differences (P less than .05) existed for calf cannon bone circumference and length before and after adjustment for gestation length and birth weight of the calf. Sire BEPD was positively associated with cannon and head circumferences independent of phenotypic birth weight and gestation length. No relationship existed between CEPD or threshold model first-calf calving ease expected progeny difference and any calf measure, either before or after adjustment for birth weight. Multivariate factor analysis was used to describe independent components of skeletal width, frame, and thickness after removal of birth weight effects; factors were not related to genetic merit for calving ease or observed calving performance. Independent of weight, newborn calf measures were not highly related to body measures at weaning or to dam birth measures. Body shape differences at constant weight existed in crossbred calves, but they were not related to sire genetic merit for calving ease or measured dystocia. Selection for calf body shape, independent of birth weight, would not reduce dystocia.

Animals↗

PubMedDate not supplied

Analysis of prevalence of presumed inherited eye diseases in Entlebucher Mountain Dogs.

We analyzed the prevalence of the presumed inherited eye diseases (PIED) noncongenital cataract and progressive retinal atrophy in the Entlebucher Mountain Dog for systematic environmental influences and the additive genetic variation. Multivariate linear animal models using residual maximum likelihood methods and multivariate threshold animal models using Gibbs sampling in Bayesian analyses were used to estimate variance and covariance components. Data were obtained from the kennel club for Swiss Mountain Dog breeds in Germany. PIED were recorded using the standardized protocols of the Dortmunder Kreis, the German panel of the European Eye Scheme for Diagnosis of Inherited Eye Diseases in Animals (DOK). The material included 515 Entlebucher Mountain Dogs from 344 litters at 77 different kennels. Veterinary diagnoses for PIED were from the years 1981-2001. Pedigree information was available for up to nine generations. The multivariate animal model regarded the fixed effects of sex, birth year, experience of the veterinary ophthalmologist, litter size, percentage of examined dogs per litter, inbreeding coefficient and age at examination. The common environment of the litter and the additive genetic effect of the animal were taken into account as randomly distributed effects. The heritability estimates for PIED in the Entlebucher Mountain Dog were h2=0.15+/-0.06 (noncongenital cataract), and h2=0.34+/-0.08 (progressive retinal atrophy) in the linear model and h2=0.32+/-0.05 (noncongenital cataract) and h2=0.59+/-0.03 (progessive retinal atrophy) in the threshold model. The additive genetic correlation between noncongenital cataract and progressive retinal atrophy was moderately positive (r(g)=0.54+/-0.08) in the threshold model. The number of examinations performed by the veterinary ophthalmologists was associated with slightly higher heritabilities for noncongenital cataract and considerably higher heritabilities for progressive retinal atrophy. The investigated PIED in the Entlebucher Mountain Dog are genetically influenced and the size of the genetic parameters estimated may be sensitive to the accuracy of the diagnosis and how the data were collected.

Animals↗

PubMed1998

From chimney sweeps to astronauts: cancer risks in the work place: the 1998 Lauriston Taylor lecture.

Percival Pott, in 1775, was the first to note an association between overt cancer and a carcinogen in the work place when he astutely observed an elevated incidence of scrotal cancer in small boys who assisted chimney sweeps. In their "workplace" astronauts and crew of high altitude jet-liners are exposed, not only to low linear energy transfer (LET) radiation but also to HZE (high energy + high atomic number) particles and to neutrons-for which no human epidemiological data exist. The current system of radiation protection is based on risk estimates from low LET radiations, delivered in large doses and at high dose-rate, coupled with the assumption of a linear no-threshold model. In extrapolating to low doses and dose-rates, and to high LET radiations, it would be helpful if the mechanisms of radiation carcinogenesis were known. Unfortunately that is not the case, though progress has been made toward that end. Many human leukemias and lymphomas appear to be due to specific chromosomal translocations, while solid tumors usually involve multiple mutations in oncogenes, deletions in suppressor genes, and/or chromosomal rearrangements. Genomic instability and immortality are hallmarks of cancer and it is attractive to hypothesize that this is due to a mutation in a gene or genes responsible for the stability of the genome. Examples abound of a small DNA change inactivating a gene and leading to major biological consequences. This could result from a single particle, especially a HZE particle, or a recoil proton from the absorption of a neutron. In this context the assumption of a threshold is hazardous, and the linear no-threshold hypothesis still appears to be prudent and conservative.

Astronauts↗

PubMed1998

Seasonal variation in birth date of children with cleft lip.

Liability to neural tube defects is increased by maternal dietary deficiency, and children with neural tube defects show a possibly related seasonal variation in date of birth. Since maternal dietary insufficiency may also increase liability to cleft lip, with or without cleft palate (CLP), we wondered if children with CLP would also show a seasonal variation in birth date. The multifactorial-threshold model predicts that any such effect would be more apparent in males than females, since CLP is more frequent in males. Month of birth was obtained from records of 598 children with CLP seen at The Montreal Children's Hospital between 1950 and 1996. Children with syndromes or associated malformations were excluded. There was a significant tendency for children with CLP to be born more often in the summer than in winter. The difference was greater in males than in females. The seasonal fluctuation in month of birth of children with CLP is consistent with the presence of an environmental factor increasing liability, with a maximal effect in November-December. This might be related, at least in part, to a seasonal fluctuation in maternal nutrition. The data support the prediction that analyzing the data for the sexes separately would amplify the effects of variation in liability for a multifactorial threshold trait that has a different frequency in males and females. This approach could be useful in the study of other gene-environment interactions.

Cleft Lip↗

PubMed2002

Setting ambient air quality standards for particulate matter.

Ambient air particulate matter (PM), unspecified as to chemical composition, is of concern because of its health effects. Air quality standards for PM have been established in many countries. The earliest standards were based on threshold models and use of a margin of safety. Initially, standards were based on the mass of total suspended material. In the 1980s a shift to a size-specific standard, PM(10), began. PM(10) is the fraction of PM captured with 50% efficiency at 10 microm and greater efficiency at smaller sizes. In the late 1990s, standards were proposed for PM(2.5), which is captured with 50% efficiency at 2.5 microm. The standards for PM are based almost exclusively on human epidemiological data, with laboratory animal and in vitro data used in a supporting role. During the 1990s, new statistical tools began to be used and demonstrated an association between increased PM and an increase in cardiorespiratory morbidity and mortality. The analyses are complicated by the effects of other pollutants such as ozone. Effects have been observed down to 10-20 microg of PM(10) per cubic meter, levels equal to or below background in many parts of the world. In many studies there has been no evidence of a threshold. In the absence of a threshold, a critical issue becomes how to determine how low is low enough? This paper reviews the current literature on PM health effects and suggests research avenues that may yield data which, combined with public policy considerations, may be able to address the issue of 'how low is low enough?'

Air↗

PubMed1975

Experimental brain damage from fluid pressures due to impact acceleration. 4. comparative studies with acceleration-concussion.

In order to elucidate the cause of brain damage in head injuries experiments are often designed to cause impacts to the intact skull of animals. To study the injurious significance of the contre-coup part of the impact acceleration pressure pattern we have previously applied direct loading through a parietal opening to the rabbit skull cavity. In order to evaluate the effects of the acceleration, similar impacts were delivered with greater magnitudes of such movements of the intact reinforced rabbit skull with the same equipment attached but without trephine opening. Varied and predictable acceleration, velocity and displacement of the head, and minimized skull deformation were possible with this model. Threshold levels of such impact acceleration were studied with regard to changes in respiratory and vasomotor activities ("concussive response"). Vascular permeability changes in the brain and spinal cord were studied with Ean's blue-albumin injection before the impact. Morphological observations were also made at the end of the experiments. No significant pathophysiological or morphological effects were elicited below peak acceleration of 2000 gn (duration 0.7 ms), peak velocity of 5 m/s or total dislocation of the head of 30 mm. At higher levels of impact a "concussive response" was elicited without fractures of the skull bone or significant brain lesions. Thus, in impact tests resulting in acceleration magnitudes far below those levels the signs of brain damage induced might mainly be related to the mechanical effects added--i.e. the fluid pressure loading.

Acceleration↗

PubMed1981

The z-model -- a proposal for spatial and temporal modeling of visual threshold perception.

By considering only the modulation transfer functions of stationary, uniformly moved, and time modulated sinusoidal gratings it is possible to derive a simple model, the "z-model", for the spatio-temporal frequency behaviour of one-dimensional patterns. The transmission function of this model is a band pass function of a single coordinate z, which is a quadratic form of the spatial and temporal frequencies (rotational symmetry with respect to space and time). The model is determined by only three constants. Optionally a time phase which accounts for delay and phase distortion can be added. This model can also be derived from reaction time measurements for switched on sinusoidal gratings. With this model the response of a wide variety of spaito-temporal patterns have been calculated and compared with measured threshold data. For two-dimensional patterns orientational filtering has to be added to the model leading to a further parameter. This model predicts satisfactorily the threshold modulation for a great variety of arbitrary spaito-temporal patterns. However the absolute threshold value for aperiodic transient patterns differs slightly in direction of smaller sensitivity as compared with periodic stationary patterns. This suggests that the peak detection scheme usually used in threshold detection modeling should be replaced by an integrative mechanism.

Mathematics↗

PubMed1986

Symptoms of anxiety and depression in a volunteer twin population. The etiologic role of genetic and environmental factors.

We examined the etiologic role of genetic and environmental factors in 14 symptoms of anxiety and depression reported by 3,798 pairs of adult twins from the Australian National Health and Medical Research Council Twin Register. Multifactorial multiple-threshold models fit the individual symptom scores well. For a substantial majority of the symptoms, the variance in liability was best explained by only genetic factors and environmental influences specific to the individual, where 33% to 46% of the variance was due to genetic factors. For four symptoms, it was not possible to choose definitively between models that, in addition to specific environment, included genetic vs familial environmental effects. These results provide strong evidence for the role of genetic factors in the etiology of symptoms of anxiety and depression as reported in a general population. Evidence for an etiologic role of familial environmental factors was much weaker. If familial environmental factors play any role in the production of these symptoms, they are more important in symptoms of depression than of anxiety, and the factors that predispose to these symptoms are only modestly correlated in males and females.

Adult↗

PubMed1999

Linkage disequilibrium on the COMT gene in French schizophrenics and controls.

Catechol-O-methyltransferase (COMT) catalyzes the degradation of catecholamines and could therefore play a role in the etiology of schizophrenia. Moreover, microdeletions including the COMT locus have been found in schizophrenics presenting typical features of the velo-cardio-facial syndrome. In the present work, five single-strand conformation polymorphisms were detected in exons of the COMT gene. The linkage disequilibria between the polymorphisms were estimated, and the genotypic frequencies were calculated on a sample of 126 to 137 schizophrenics and 136 to 140 controls, depending on the marker. Patients and controls were matched for ethnicity and geographical origin. A trend toward association was found between schizophrenia and (i) genotype 11 of the Pml I polymorphism (p = 0.034; OR = 1.82); (ii) haplotype 1-2 for the Pml I and Bcl I polymorphisms (p = 0.022; OR = 1.75). The Pml I polymorphism is in complete linkage disequilibrium with the common Met-->Val(158) substitution, which affects the activity of the enzyme. This finding suggests a possible minor effect of COMT in a multifactorial threshold model of vulnerability to schizophrenia.

3' Untranslated Regions↗

PubMed1997

Effect of multifactorial genetic liability to exencephaly on the teratogenic effect of valproic acid in mice.

The present study shows that the multifactorial genetic liability to spontaneous exencephaly in the SELH/Bc mouse strain (10-20% of embryos) also confers an elevated risk of exencephaly induced by valproic acid. Treatment of pregnant dams (600 mg/kg sodium valproate in distilled water, i.p.) during the critical period on day 8 (D8) of gestation resulted in D14 exencephaly frequencies of 69% in SELH/Bc contrasted with 39% in each of the SWV/Bc and ICR/Bc strains. Analysis of these data under the assumptions of the threshold model indicated that the valproic acid-induced-shift in mean liability was similar for all three strains, and therefore the effects of genotype and teratogen were additive, not synergistic. A similar exencephaly response pattern for the same three strains was observed previously with retinoic acid [Tom et al. (1991) Teratology 43:27-40], a pattern that, combined with the data of Finnell et al. [(1988) Teratology 38:313-320], argues that strain differences in exencephaly response are not due to strain differences in teratogen metabolism. SWV/Bc and ICR/Bc embryos differ in location of the Closure 2 initiation site of cranial neural tube closure [Juriloff et al. (1991) Teratology 44:225-233], but the observation that they do not differ in risk of exencephaly produced by either valproic acid or retinoic acid contradicts the hypothesis that this particular morphological difference underlies strain differences in exencephaly risk. The high exencephaly response of SELH/Bc to two teratogens predicts that human conceptuses with a genetically determined elevated risk for neural tube defects could be easily tipped into high risk by mild teratogens.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Risk of recurrence of craniospinal anomalies.

The authors analyzed 1,655 situations from their Genetic Counseling Service over a 15 year period where the reason for counseling was craniospinal anomaly (neural tube defects and/or hydrocephalus) in the family. Excluding the obviously monogenically inherited cases, they investigated pregnancies undertaken after 1,285 isolated and 177 multiple forms of craniospinal abnormalities. The recurrence rate of craniospinal defects was found to be 3.66%, which is about ten times higher than the general population risk, supporting the theory of the multifactorial threshold model in the inheritance of these anomalies. The recurrence risks of neural tube defects and of hydrocephalus were 3.47% and 2.95%, respectively. The authors concluded that recurrence risk is mainly influenced by the pathoanatomic severity of the involved anomaly, the degree of relationship, and the number of affected relatives in the family. There is a positive correlation between the pathoanatomic severity of the anomaly in the proband and the offspring. At least in one-half of the cases the same type of anomaly was observed again in the offspring as in the proband. Attention is drawn to the fact that hydrocephalus (ventriculomegaly) is often manifested only in the second half of gestation. Therefore, performing ultrasound examination is strongly recommended not only at the 18th but at the 24th week of gestation, as well in pregnancies with a positive history of neural tube defects and/or hydrocephalus.

Family Health↗

PubMed1979

A family study of congenital inguinal hernia.

In fathers and mothers of 707 index patients with operated indirect congenital inguinal hernia (CIH) born in Budapest during the years 1962-1966 the frequency of CIH was two and five to six times higher, respectively, than in the general population. The rate of affected sibs was higher than that of parents but was greatly dependent on the sex of the index patient. Heritability estimates of CIH vary significantly in parents (0.35 +/- 0.12) and in sibs (0.78 +/- 0.14). In twins the heritability is 0.77. These data agree with the multifactorial threshold model involving dominance variance.

Adult↗

PubMed1985

Fetal mortality in sibships with one or more affected members with oral clefts.

We investigated the fetal mortality in 903 sibships with at least one member having cleft lip with or without cleft palate [CL(P)] and 213 with at least one individual affected with cleft palate (CP) derived from three different data sources in México. The frequency of fetal wastage (abortion and/or stillbirth) was not increased in sibships where the propositi had cleft lip and palate (CLP) as compared with cleft lip (CL) nor in those where index cases had a bilateral lesion as compared to a unilateral one, nor when the index cases with CL(P) were female rather than males, nor when the index case was a female with bilateral lesion as compared to males with a unilateral one. Similarly fetal mortality was not increased in sibships in which the propositus had CP compared to those in which the index case was a female. These findings are contrary to some reports that claim to support a two-threshold model according to which individuals reaching the first one would be born with an oral cleft, and those reaching the second would be aborted. Our results, together with others, suggest the possibility that liability to oral clefts is independent of liability to fetal wastage.

Abortion, Spontaneous↗

PubMed1990

Angular homeostasis: VI. Threshold processes with bivariate liabilities.

The general structure of the threshold model of multifactorial determination is discussed. It is supposed that in place of a single liability (in Falconer's sense) there are two separate liabilities; and whether or not the pathological trait is present depends on a non-additive interaction between the liabilities, so that the region has curved boundaries. The genetics of ontogeny of a process involving spatial orientation (e.g., cardiac ontogeny) is used as a substantive illustration. Genetic analysis of the trait (as contrasted with the liabilities) yields results that on the one hand may seem quite counterintuitive, yet on the other hand they correspond to the kind of bizarre patterns encountered in quasi-empirical genetic counseling for cleft palate or neural tube defect. The impact of refinement of phenotype made possible by non-invasive methods is sketched. This model can be generalized to any number of liabilities, independent or not.

Embryonic and Fetal Development↗

PubMed1993

Segregation analysis of hypospadias: a reanalysis of published pedigree data.

Little is known about the cause of hypospadias, one of the most common urogenital anomalies in males. Familial clustering of hypospadias is well recognized, with heritability estimated to be about 70% under a simple multifactorial threshold model. Neither alternative genetic mechanisms nor shared environmental factors within families have been explored fully. To learn more about possible genetic mechanisms, we used 2 methods of segregation analysis to analyze a set of published family data. These analyses are based on the families of 103 probands with hypospadias, who were ascertained through surgery departments in Denmark [Sørensen, 1953]. Urogenital examinations were performed on 95% (n = 1,510) of available male relatives, and 2.2% were found to have hypospadias. Within the probands' nuclear families, 12% of nonproband sons of normal fathers were affected. Using the mixed model of inheritance, both the autosomal dominant (AD) and codominant models fit these data better than either autosomal recessive (AR) or multifactorial models. Using the regressive logistic models, both AD and AR models were equally likely, and a model of nonMendelian sibship clustering gave a better fit to these data. These inconsistent findings illustrate the difficulties commonly encountered in segregation analysis. Using 2 different statistical approaches, we found 2 different explanations, both of which differ from the autosomal recessive model originally suggested by Sørensen [1953]. Hypospadias in these families is almost certainly heterogeneous. Determining the cause of familial clustering of hypospadias will require careful delineation of persons with recognized syndromes from uncomplicated cases and detailed information on potential prenatal risk factors.

Female↗

PubMed1994

Spontaneous abortion--high risk factor for neural tube defects in subsequent pregnancy.

An increased spontaneous abortion rate has been observed in pregnancies preceding that of fetuses or newborn infants with neural tube defects (NTDs). There are 2 suggested explanations for this observation. One is that a trophoblastic cell rest, remaining from a previous aborted pregnancy, interferes with normal embryogenesis. The second is that the previous lost fetus was affected with NTD. We studied the obstetric history of mothers of newborn infants with NTDs compared to those with other birth defects, in low and high risk groups for NTD (Jew and Bedouins). A significantly higher spontaneous abortion rate (48%) in the preceding pregnancy was found in the NTD group compared to the group with other birth defects (20%). This was especially remarkable for spina bifida cases in the Jewish study population. A significantly higher rate of preceding spontaneous abortion was also found in congenital heart defects (CHD) when compared to other congenital malformations. A hypothesis based on the multifactorial threshold model is put forward to explain these findings. Based on the realization that spontaneous abortion constitutes a high risk factor for NTD and possibly also CHD, we recommend a delay of subsequent pregnancy and periconceptional treatment with folic acid following spontaneous abortion.

Abortion, Spontaneous↗

PubMed1994

Genetics of blood-injury fears and phobias: a population-based twin study.

Data on unreasonable fears of blood, needles, hospitals, and illness (BNHI) were collected by telephone interview from 541 MZ and 388 DZ pairs of female twins from the population-based Virginia Twin Registry. BNHI phobia was defined as the presence of fear accompanied by interference. Age at onset of phobia was found to be very similar to that of situational phobias previously assessed in the sample. Using a multiple threshold model, we found no evidence for qualitative differences between BNHI fears and BNHI phobia. The familial aggregation of fears appears to be entirely due to additive genetic variance. The possible exception to this is fear of illness, which, like BNHI phobias, seems to aggregate within families because of shared environmental factors. Although power to discriminate between the causes of familial resemblance is low, results suggest that random traumatic events and some social learning may be responsible for the onset of BNHI phobias. About two-thirds of variance is individual-specific environmental, and could include genotype x environment interaction and measurement error.

Age of Onset↗