Evidence for a Type 1 diabetes‐specific mechanism for the insulin gene‐associated IDDM2 locus rather than a general influence on autoimmunity

Aims The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5′ upstream of the insulin (INS) and insulin‐like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self‐tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes‐specific locus or acting as a general autoimmunity gene. Methods We genotyped the INS‐IGF2 VNTR [using the surrogate INS?23 HphI single nucleotide polymorphism (SNP)] in 823 Graves’ disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. Results We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case–control dataset showed no genotypic or allelic difference between the two populations. Conclusions These data suggest that the INS‐IGF2 VNTR is acting as a Type 1 diabetes‐specific susceptibility gene rather than as an influence on general autoimmunity.     

The genetic epidemiology of phobias in women. The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia.

In 2163 personally interviewed female twins from a population-based registry, the pattern of age at onset and comorbidity of the simple phobias (animal and situational)--early onset and low rates of comorbidity--differed significantly from that of agoraphobia--later onset and high rates of comorbidity. Consistent with an inherited "phobia proneness" but not a "social learning" model of phobias, the familial aggregation of any phobia, agoraphobia, social phobia, and animal phobia appeared to result from genetic and not from familial-environmental factors, with estimates of heritability of liability ranging from 30% to 40%. The best-fitting multivariate genetic model indicated the existence of genetic and individual-specific environmental etiologic factors common to all four phobia subtypes and others specific for each of the individual subtypes. This model suggested that (1) environmental experiences that predisposed to all phobias were most important for agoraphobia and social phobia and relatively unimportant for the simple phobias, (2) environmental experiences that uniquely predisposed to only one phobia subtype had a major impact on simple phobias, had a modest impact on social phobia, and were unimportant for agoraphobia, and (3) genetic factors that predisposed to all phobias were most important for animal phobia and least important for agoraphobia. Simple phobias appear to arise from the joint effect of a modest genetic vulnerability and phobia-specific traumatic events in childhood, while agoraphobia and, to a somewhat lesser extent, social phobia result from the combined effect of a slightly stronger genetic influence and nonspecific environmental experiences.     

A twin-family study of self-report symptoms of panic-phobia and somatization

Self-report symptoms of anxiety are widely used in mental health and social science research as an index of current psychiatric state. Previous twin studies have suggested that genetic factors account for a significant proportion of the variance in these symptoms. To replicate and extend these findings, we examined self-report symtoms of panic-phobia and somatization in the “Virginia 30,000” twin-family sample. Model fitting applied to 80 unique relationships in the twin-family pedigree produced the following major results: (i) genetic effects were significant for both symptom factors, accounting for between 25 and 49% of the total variance, with the exception of symptoms of panic-phobia in females, where they accounted for 15–16% of the variance; (ii) familial environmental effects were absent for symptoms of somatization, while for symptoms of panic-phobia they accounted for a very small proportion of variance in males (≤1.2%) and a modest proportion in females (6–17%) (iii) spousal correlations were present for both factors, ranging from +0.05 to +0.20; (iv) genetic factors which influenced symptoms were generally the same in males and females, although their effect was greater in males; (v) heritability estimates were lower in the population-based than in the volunteer sample; and (vi) when test-retest reliability was included in the model, results suggest that genetic factors account for at least half of the stable variance for all symptom factors, except panic-phobia in females. Our results support the validity of previous twin studies of self-report symptoms of anxiety and suggest that genetic factors significantly influence these symptoms but familial-environmental factors play little or no etiologic role.     

Testing genetic models for multiple symptoms: An application to the genetic analysis of liability to depression

A model is presented which allows for the contribution of genes and environment to categorical data on multiple symptoms. The model distinguishes between parameters needed to express the relationship between a latent trait and observed responses and the parameters required to represent the causes of variation in the latent trait. The regression of the latent trait on covariates may also be specified. The model is applied to symptoms of depression in 1983 pairs of adult female monozygotic and dizygotic twins. A model which allows only for polygenic variation in the latent trait is supported as well as the mixed model, which also allows for the effects of a major gene. The likelihood is significantly lower when all genetic effects are ascribed to a single gene. Practical limitations of the method are discussed.This research is supported by Grants AG04954, AA06781, GM32782, GM30250, and MH40828 from the National Institutes of Health. We are indebted to Dr. Greg Carey for his incisive discussion.     

Tobacco, alcohol and drug use in eight- to sixteen-year-old twins: the Virginia Twin Study of Adolescent Behavioral Development.

OBJECTIVE: This study reports prevalences of lifetime and current alcohol, tobacco and drug use in adolescents; examines associations between substance use and a number of putative risk factors; and estimates the contribution of genetic, shared and unique environmental influences on substance use. METHOD: Substance use data were collected using the Child and Adolescent Psychiatric Assessment on a population sample of 1,412 male and female monozygotic and dizygotic twin pairs, aged 8 through 16, from the Virginia Twin Study of Adolescent Behavioral Development. RESULTS: Heritabilities were estimated to be 84% and 82% for liability to lifetime and current tobacco use, respectively. For alcohol use the role of genes and environment varied according to the context of reporting. Liability to lifetime alcohol use was estimated to be under environmental control, with 71% of the variation shared by members of a twin pair and 29% unique to individual twins. Lifetime alcohol use without the permission of a parent or guardian and current use of alcohol were predominantly explained by genetic factors (h2 = 72% and 74%). The role of genetic factors increased and that of unique environmental factors decreased with increasing severity of alcohol use. Lifetime use of any drug showed a heritability of 45%, with the shared environment accounting for 47% of the variation. Shared environmental factors explained most of the variation in marijuana use. CONCLUSIONS: Genetic factors explained a significant proportion of the variation in the use of tobacco, alcohol and other drugs. Shared environmental factors contributed significantly to lifetime alcohol use and other drug use.     

NOD/SCID mice engineered to express human IL-3, GM-CSF and Steel factor constitutively mobilize engrafted human progenitors and compromise human stem cell regeneration.

Transplantation of immunodeficient mice with human hematopoietic cells has greatly facilitated studies of the earliest stages of human hematopoiesis. These include demonstration of the ability of injected 'human-specific' hematopoietic growth factors to enhance the production of human cells at multiple levels of differentiation. In contrast, the effects of continuous exposure to such molecules have not been well investigated. Here, we show that nonobese diabetic severe combined immunodeficiency mice genetically engineered to produce ng/ml serum levels of human interleukin-3 (IL-3), granulocyte/macrophage-stimulating factor (GM-CSF) and Steel factor (SF) display a complex phenotype when transplanted with primitive human bone marrow (BM) or fetal liver cells. This phenotype is characterized by an enhancement of terminal human myelopoiesis and a matched suppression of terminal human erythropoiesis, with a slight reduction in human B-lymphopoiesis in the BM of the engrafted mice. Human clonogenic progenitors are more prevalent in the blood of the transplanted growth factor-producing mice and this is accompanied by a very marked reduction of more primitive human cells in the BM. Our findings suggest that long-term exposure of primitive human hematopoietic cells to elevated levels of human IL-3, GM-CSF and SF in vivo may deleteriously affect the stem cell compartment, while expanding terminal myelopoiesis.     

BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice.

In this study, we describe the successful use of a gene transfer approach to demonstrate the ability of forced BCR-ABL expression to deregulate the growth and differentiation of primitive naive human hematopoietic cells after their transplantation into immunodeficient mice. Human CD34+ cord blood cells were exposed to an MSCV retrovirus containing a BCR-ABL-IRES-GFP (P210) cassette and then injected immediately into sublethally irradiated nonobese diabetic-severe combined immunodeficiency (NOD/SCID) or NOD/SCID-beta2microglobulin-/- mice. P210- and control-transduced (GFP+) human hematopoietic cells were produced in the bone marrow of the mice at similar levels until termination of the experiments 5-6 months later. However, the P210-transduced cells produced a markedly different spectrum of progeny, with an increased ratio of myeloid to B-lymphoid cells and a frequently prolonged increase in erythroid and megakaryocytic cells. After 5 months, several of the mice transplanted with P210-transduced cells developed an increased WBC count and/or splenomegaly due to an expansion of the human GFP+ population. These findings demonstrate that forced expression of BCR-ABL in primitive transplantable human hematopoietic cells is sufficient to cause a rapid and persistent deregulation of their growth and differentiation in vivo with occasional evidence after several months of progression to an early stage of disease.