Multifactorial Threshold Model Research Articles

Family environment and polygenic risk in the bipolar high-risk context.

The interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high-risk offspring perceptions of their family environment (FE). We tested the association of offspring-perceived FE in interaction with BD-PRS on liability for BD in offspring at high or low familial risk for BD. Offspring of a parent with BD (oBD; n=266) or no psychiatric disorders (n=174), aged 12-21 at recruitment, participated in the US and Australia. Empirically-derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD-PRS were derived from Psychiatric Genomics Consortium BD-GWAS. Lifetime DSM-IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes. Fifty-two offspring were diagnosed with BD. For those with well-functioning FE (two-thirds of the sample), higher BD-PRS tracked positively with liability for BD. However, for those with high-conflict FEs, the relationship between BD-PRS and liability to BD was negative, with highest risk for BD observed with lower BD-PRS. In exploratory analyses, European-ancestry offspring with BDhad elevated history of suicidal ideation in high-conflict FE compared towell-functioning-FE, and of suicide attempt with low-BD-PRS and high-conflictFE. The data suggest that the relationship of BD-PRS and offspring liability for BD differed between well-functioning versus high-conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.

1059 FAMILIAL RISK OF DILATED AND HYPERTROPHIC CARDIOMYOPATHY: A NATIONAL FAMILY STUDY IN SWEDEN

Abstract Aims To determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first-, second- and third-degree relatives of affected individuals. Methods and results In this population-based multigenerational cohort study, full-siblings, half-siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included and register-based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6,334,979 subjects and consisted of 5,577,449 full-siblings, 1,321,414 half-siblings, and 3,952,137 cousins. Overall, 10,272 (0.16%) unique individuals were diagnosed with DCM and 3,769 (0.06%) with HCM. Of these, 7,716 (75.12%) and 2,375 (63.01%) were males, respectively. Familial risk odds ratios (ORs) for DCM were 5.35 (95% confidence intervals (CI): 4.85-5.90) for full-siblings, 2.68 (95%CI:1.86-3.87) for half-siblings, and 1.72 (95%CI:1.12-2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95%CI:37.66-47.82) for full-siblings, 32.70 (95%CI:21.32-50.15) for half-siblings, and 36.96 (95%CI:29.50-46.31) for cousins of affected individuals. In sex-stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. Conclusions Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.

Familial risk of dilated and hypertrophic cardiomyopathy: a national family study in Sweden.

This study aims to determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first-degree, second-degree, and third-degree relatives of affected individuals. In this population-based multigenerational cohort study, full-siblings, half-siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included, and register-based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6 334 979 subjects and consisted of 5 577 449 full-siblings, 1 321 414 half-siblings, and 3 952 137 cousins. Overall, 10 272 (0.16%) unique individuals were diagnosed with DCM and 3769 (0.06%) with HCM. Of these, 7716 (75.12%) and 2375 (63.01%) were males, respectively. Familial risk ORs for DCM were 5.35 [95% confidence intervals (CI): 4.85-5.90] for full-siblings, 2.68 (95% CI:1.86-3.87) for half-siblings, and 1.72 (95% CI:1.12-2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95% CI:37.66-47.82) for full-siblings, 32.70 (95% CI:21.32-50.15) for half-siblings, and 36.96 (95% CI:29.50-46.31) for cousins of affected individuals. In sex-stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.

Understanding interactions between risk factors, and assessing the utility of the additive and multiplicative models through simulations.

Understanding the genetic background of complex diseases requires the expansion of studies beyond univariate associations. Therefore, it is important to use interaction assessments of risk factors in order to discover whether, and how genetic risk variants act together on disease development. The principle of interaction analysis is to explore the magnitude of the combined effect of risk factors on disease causation. In this study, we use simulations to investigate different scenarios of causation to show how the magnitude of the effect of two risk factors interact. We mainly focus on the two most commonly used interaction models, the additive and multiplicative risk scales, since there is often confusion regarding their use and interpretation. Our results show that the combined effect is multiplicative when two risk factors are involved in the same chain of events, an interaction called synergism. Synergism is often described as a deviation from additivity, which is a broader term. Our results also confirm that it is often relevant to estimate additive effect relationships, because they correspond to independent risk factors at low disease prevalence. Importantly, we evaluate the threshold of more than two required risk factors for disease causation, called the multifactorial threshold model. We found a simple mathematical relationship (square root) between the threshold and an additive-to-multiplicative linear effect scale (AMLES), where 0 corresponds to an additive effect and 1 to a multiplicative. We propose AMLES as a metric that could be used to test different effects relationships at the same time, given that it can simultaneously reveal additive, multiplicative and intermediate risk effects relationships. Finally, the utility of our simulation study was demonstrated using real data by analyzing and interpreting gene-gene interaction odds ratios from a rheumatoid arthritis case-control cohort.

Msx1 Heterozygosity in Mice Enhances Susceptibility to Phenytoin-Induced Hypoxic Stress Causing Cleft Palate.

Cleft palate is among the most frequent congenital defects in humans. While gene-environment multifactorial threshold models have been proposed to explain this cleft palate formation, only a few experimental models have verified this theory. This study aimed to clarify whether gene-environment interaction can cause cleft palate through a combination of specific genetic and environmental factors. Msx1 heterozygosity in mice (Msx1+/-) was selected as a genetic factor since human MSX1 gene mutations may cause nonsyndromic cleft palate. As an environmental factor, hypoxic stress was induced in pregnant mice by administration of the antiepileptic drug phenytoin, a known arrhythmia inducer, during palatal development from embryonic day (E) 11 to E14. Embryos were dissected at E13 for histological analysis or at E17 for recording of the palatal state. Phenytoin administration downregulated cell proliferation in palatal processes in both wild-type and Msx1+/- embryos. Bone morphogenetic protein 4 (Bmp4) expression was slightly downregulated in the anterior palatal process of Msx1+/- embryos. Although Msx1+/- embryos do not show cleft palate under normal conditions, phenytoin administration induced a significantly higher incidence of cleft palate in Msx1+/- embryos compared to wild-type littermates. Our data suggest that cleft palate may occur because of the additive effects of Bmp4 downregulation as a result of Msx1 heterozygosity and decreased cell proliferation upon hypoxic stress. Human carriers of MSX1 mutations may have to take more precautions during pregnancy to avoid exposure to environmental risks.

Hyperstimulation of the immune system as a cause of autoimmune diseases

The pathogenesis of autoimmune diseases is very complex and multi-factorial. The concept of Mosaics of Autoimmunity was introduced to the scientific community 30 years ago by Y. Shoenfeld and D.A. Isenberg, and since then new tiles to the puzzle are continuously added. This concept specifies general pathological ideas about the multifactorial threshold model for polygenic inheritance with a threshold effect by the action of a number of external causal factors as applied to the field of autoimmunology. Among the external factors that can excessively stimulate the immune system, contributing to the development of autoimmune reactions, researchers are particularly interested in chemical substances, which are widely used in pharmacology and medicine. In this review we highlight the autoimmune dynamics i.e. a multistep pathogenesis of autoimmune diseases and the subsequent development of lymphoma in some cases. In this context several issues are addressed namely, genetic basis of autoimmunity; environmental immunostimulatory risk factors; gene/environmental interaction; pre-clinical autoimmunity with the presence of autoantibodies; and the mechanisms, underlying lymphomagenesis in autoimmune pathology. We believe that understanding the common model of the pathogenesis of autoimmune diseases is the first step to their successful management.

Variation at DENND1B and Asthma on the Island of Tristan da Cunha.

A high prevalence of asthma has been documented among the inhabitants of Tristan da Cunha, an isolated island in the South Atlantic. The population derives from just 28 founders. We performed lung function testing, including methacholine inhalation challenge, allergen skin prick testing, and collected DNA from essentially all of the current island population (269 individuals), and genotyped a panel of 43 single-nucleotide polymorphisms (SNPs) reported as associated with asthma and atopy. We carried out a mixed-model association analysis using the known pedigree. There were 96 individuals diagnosed as asthmatic (36%), and heritability estimates were similar to those from nonisolated population samples (multifactorial threshold model, h2 = 48%). The first component from a genetic principal components analysis using the entire SNP panel was nonlinearly associated with asthma, with the maximum risk to those intermediate to reference (Human Genome Diversity Project) European and African samples means. The single most strongly associated SNP was rs2786098 (p = 5.5 × 10-5), known to regulate the gene DENND1B. This explained approximately one-third of the trait heritability, with an allelic odds ratio for the A allele of 2.6. Among A/A carriers, 10 out of 12 individuals were asthmatic. The rs2786098*A variant was initially reported to decrease the risk of childhood (atopic) asthma in European but slightly increase the risk in African-descended populations, and does significantly alter Th2 cell function. Despite an absence of overall association with this variant in recent asthma genome wide association studies meta-analyses, an effect may exist on the particular genetic background of the Tristan da Cunha population.

The Latent Taxonicity of Schizotypy in Biological Siblings of Probands With Schizophrenia.

If schizotypy is a taxonic liability for schizophrenia with a general population prevalence of ~10%, it should also be taxonic among biological siblings of probands with schizophrenia. Moreover, assuming this is so, siblings' schizotypy class membership should be predicted by probands' familial load for psychotic disorder and clinical severity, consistent with a multifactorial polygenic threshold model of schizophrenia. We tested these hypotheses in the Genetic Risk and Outcome of Psychosis (GROUP) Study where siblings of probands (n = 792) and unaffected controls (n = 559) provided self-report ratings on the Community Assessment of Psychic Experiences (CAPE). Maximum covariance analyses of control group ratings led to the identification of CAPE items sensitive to nonredundant positive and negative schizotypy classes in the control group (prevalence = 7.9% and 11.1%, respectively). When the same taxonic solution was applied to siblings' CAPE rating, taxometric analyses yielded evidence for larger positive and negative schizotypy classes among siblings (prevalence = 14.1% and 21.8%, respectively). Whereas probands' familial loads for bipolar disorder or drug use disorders did not predict siblings' membership in the schizotypy classes, probands' familial load for psychotic disorder did. Siblings were more likely to be members of the positive schizotypy class where their probands were more severely affected. The pattern of findings is consistent with Meehl's argument that schizotypy reflects liability for schizophrenia.

Irving I. Gottesman (1930-2016): the multifactorial threshold model of complex phenotypes mediated by endophenotype strategies.

Irving I. Gottesman (1930-2016): the multifactorial threshold model of complex phenotypes mediated by endophenotype strategies.

Interplay between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study.

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS). Data were utilised from the Genes and Psychosis (GAP) study set in South London, UK. The GAP sample comprises 285 first-presentation psychosis cases and 256 unaffected controls with information on childhood adversity. We studied only white subjects (80 cases and 110 controls) with PRS data, as the PRS has limited predictive ability in patients of African ancestry. The occurrence of childhood adversity was assessed with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the PRS was based on genome-wide meta-analysis results for schizophrenia from the Psychiatric Genomics Consortium. Higher schizophrenia PRS and childhood adversities each predicted psychosis status. Nevertheless, no evidence was found for interaction as departure from additivity, indicating that the effect of polygenic risk scores on psychosis was not increased in the presence of a history of childhood adversity. These findings are compatible with a multifactorial threshold model in which both genetic liability and exposure to environmental risk contribute independently to the etiology of psychosis.

On the origins of autism: The Quantitative Threshold Exposure hypothesis

The Quantitative Threshold Exposure (QTE) hypothesis is a multifactorial threshold model that accounts for the cumulative effects of risk factor exposure in both the causation of autism spectrum disorder (ASD) and its dramatic increase over the past 30years. The QTE hypothesis proposes that ASD is triggered by the cumulative effects of high-level exposure to endogenous and environmental factors that act as antigens to impair normal immune system (IS) and associated central nervous system (CNS) functions during critical developmental stages. The quantitative threshold parameters that comprise a cumulative risk for the development of ASD are identified by the assessment of documented epidemiological factors that, in sum, determine the likelihood that ASD will occur as a result of their effects on critically integrated IS and CNS pathways active during prenatal, neo-natal and early childhood brain maturation. The model proposes an explanation for the relationship between critical developmental stages of brain/immune system development in conjunction with the quantitative effects of genetic and environmental risk factors that may interface with these critical developmental windows. This model may be useful even when the individual contributions of specific risk factors cannot be quantified, as it proposes that the combined quantitative level of exposure to risk factors for ASD rather than exposure to any one risk factor per se defines threshold occurrence rates.

What have we learned from the Psychiatric Genomics Consortium.

Decades of research in the pre-molecular genetics era firmly established that major psychiatric disorders are highly to moderately heritable, but only with the emergence of molecular genetic technology about 35 years ago was it possible to envisage identifying the specific pathogenic genes responsible. In psychiatry, the opportunity to probe pathophysiology using DNA seemed particularly attractive given that other biomedical approaches had been frustrated by the complexity of the brain, the challenges in obtaining access to fresh tissue, and the extensive potential for reverse causal associations due to the many environmental and behavioural consequences of the disorders. Simple in concept, translating heritability to pathophysiology has proven arduous. This paper provides a perspective on that process, how some of the obstacles have been overcome, and some of the implications of the current findings. The focus is the work of the Psychiatric Genomics Consortium (PGC), whose main impacts relate to common rather than rare genetic variation. This reflects the data available rather than any ideological position that rare genetic variation is unimportant in psychiatry.

Remembered: F. Clarke Fraser

Remembered: F. Clarke Fraser

Evaluating the missing heritability of bipolar disorder using the multifactorial liability threshold model

In order to evaluate the missing heritability of bipolar disorder, we queried the GWAS catalog of National Human Genome Research Institute, retrieve all the susceptible gene variation of bipolar disorder, and calculate the heritability explanation degree of each susceptibility variant using the multifactorial liability threshold model. The total heritability explanation degree of bipolar disorder was obtained through summing up the heritability explanation degree of each susceptibility variant. Then, we evaluated the missing heritability of bipolar disorder based on the total heritability explanation degree. The results showed that the total heritability explanation degree of bipolar disorder explained by known susceptible variants was 38.34%, and the other 61.66% of heritability can't be explained by known susceptibility variants, which belong to the missing heritability of bipolar disorder. The total heritability explanation degree of bipolar disorder in this study was significantly increased compared to earlier similar studies abroad. With constant discovery of new bipolar disorder susceptibility variants, the missing heritability of bipolar disorder has been greatly reduced, but the missing heritability of bipolar disorder still exists and occupies a large part of the bipolar disorder heritability, indicating that the molecular genetic mechanisms of bipolar disorder need to be further clarified.

Maternal hypertension with nifedipine treatment associated with a higher risk for right-sided obstructive defects of the heart: a population-based case–control study

ObjectiveTo establish possible aetiological factors contributing to congenital heart defects (CHD) overall and separately for different types of CHD, as causes are unknown for the vast majority of patients.DesignTo estimate...

Polygenic Threshold Model with Sex Dimorphism in Adolescent Idiopathic Scoliosis: The Carter Effect

Adolescent idiopathic scoliosis occurs between two and ten times more frequently in females than in males. The exact cause of this sex discrepancy is unknown, but it may represent a difference in susceptibility to the deformity. If this difference is attributable to genetic factors, then males with adolescent idiopathic scoliosis would need to inherit a greater number of susceptibility genes compared with females to develop the deformity. Males would also be more likely to transmit the disease to their children and to have siblings with adolescent idiopathic scoliosis. Such a phenomenon is known as the Carter effect, and the presence of such an effect would support a multifactorial threshold model of inheritance. One hundred and forty multiplex families in which more than one individual was affected with adolescent idiopathic scoliosis were studied. These families contained 1616 individuals, including 474 individuals with adolescent idiopathic scoliosis and 1142 unaffected relatives. The rates of transmission from the 122 affected mothers and from the twenty-eight affected fathers were calculated, and the prevalence among siblings was determined in the nuclear families of affected individuals. The prevalence of adolescent idiopathic scoliosis in these multiplex families was lowest in sons of affected mothers (36%, thirty-eight of 105) and highest in daughters of affected fathers (85%, twenty-two of twenty-six). Affected fathers transmitted adolescent idiopathic scoliosis to 80% (thirty-seven) of forty-six children, whereas affected mothers transmitted it to 56% (133) of 239 children (p < 0.001). Siblings of affected males also had a significantly higher prevalence of adolescent idiopathic scoliosis (55%, sixty-one of 110) compared with siblings of affected females (45%, 206 of 462) (p = 0.04). This study demonstrates the presence of the Carter effect in adolescent idiopathic scoliosis. This pattern can be explained by polygenic inheritance of adolescent idiopathic scoliosis, with a greater genetic load required for males to be affected.

Mouse as a model for multifactorial inheritance of neural tube defects

Neural tube defects (NTDs) such as spina bifida and anencephaly are some of the most common structural birth defects found in humans. These defects occur due to failures of neurulation, a process where the flat neural plate rolls into a tube. In spite of their prevalence, the causes of NTDs are poorly understood. The multifactorial threshold model best describes the pattern of inheritance of NTDs where multiple undefined gene variants interact with environmental factors to cause an NTD. To date, mouse models have implicated a multitude of genes as required for neurulation, providing a mechanistic understanding of the cellular and molecular pathways that control neurulation. However, the majority of these mouse models exhibit NTDs with a Mendelian pattern of inheritance. Still, many examples of multifactorial inheritance have been demonstrated in mouse models of NTDs. These include null and hypomorphic alleles of neurulation genes that interact in a complex fashion with other genetic mutations or environmental factors to cause NTDs. These models have implicated several genes and pathways for testing as candidates for the genetic basis of NTDs in humans, resulting in identification of putative pathogenic mutations in some patients. Mouse models also provide an experimental paradigm to gain a mechanistic understanding of the environmental factors that influence NTD occurrence, such as folic acid and maternal diabetes, and have led to the discovery of additional preventative nutritional supplements such as inositol. This review provides examples of how multifactorial inheritance of NTDs can be modeled in the mouse.

Possible multifactorial etiology of isolated microtia/anotia—A population-based study

ObjectiveTo test the possible multifactorial-threshold model in the origin of isolated microtia/anotia (IMA). MethodThe observed number of IMA in the first degree relatives of cases affected was compared with the expected number of affected first degree relatives based on the multifactorial-threshold model in the population-based large dataset of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996. ResultsOf 354 cases with IMA, 14 (4.0%) had the affected first degree relatives with IMA. There was a low and similar rate of familial occurrence of IMA in parents and siblings of cases. The observed numbers of affected first degree relatives of cases with IMA and their expected numbers did not show significant difference (p=0.47). Some other findings (e.g. male excess and the interaction of triggering environmental factors with polygenic predisposition) confirmed this hypothesis. ConclusionsThe familial pattern of cases with IMA does not reject the hypothesis that the multifactorial-threshold model, i.e. gene–environmental interaction, may be the explanation for the origin of this congenital abnormality group, although the number of familial cases was quite small in the study.

Paradox of schizophrenia genetics: is a paradigm shift occurring?

BackgroundGenetic research of schizophrenia (SCZ) based on the nuclear genome model (NGM) has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM) but not in the NGM.MethodsWe deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011) were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed.Results19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date.ConclusionThe central paradox of SCZ genetics and the results of association studies to date argue against the NGM, and in its place the MGM is emerging as a viable option to account for genomic and pathophysiological research findings involving SCZ.

Contribution of nonprimate animal models in understanding the etiology of schizophrenia.

Schizophrenia is a severe psychiatric disorder that is characterized by positive and negative symptoms and cognitive impairments. The etiology of the disorder is complex, and it is thought to follow a multifactorial threshold model of inheritance with genetic and neurodevelop mental contributions to risk. Human studies are particularly useful in capturing the richness of the phenotype, but they are often limited to the use of correlational approaches. By assessing behavioural abnormalities in both humans and rodents, nonprimate animal models of schizophrenia provide unique insight into the etiology and mechanisms of the disorder. This review discusses the phenomenology and etiology of schizophrenia and the contribution of current nonprimate animal models with an emphasis on how research with models of neuro transmitter dysregulation, environmental risk factors, neurodevelopmental disruption and genetic risk factors can complement the literature on schizophrenia in humans.