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PubMed2025

Shared genetic risk and causal associations between Post-traumatic stress disorder and migraine with antithrombotic agents and other medications.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that frequently co-occurs with pain disorders including migraine. There are proposed biological, genetic and environmental factors associated with both PTSD and migraine suggesting shared etiology. Genome-Wide Association Studies (GWAS) have been used to identify genomic risk loci associated with various disorders and to investigate genetic overlap between traits. There is a significant genetic correlation between PTSD and migraine with no evidence of a causal relationship that could be attributed to pleiotropy. Cross-disorder genetic analyses were applied to investigate the genetic overlap and causal associations using GWAS summary statistics of PTSD (n = 214408), migraine (n = 873341) and 23 medication use traits (n = 78808-305913) including anti-depressants, anti-migraine preparations and beta-blocking agents. Across the entire genome, anti-thrombotic agents had a significant and negative genetic correlation with PTSD (rG = -0.2, P FDR = 0.032) and a positive genetic correlation with migraine (rG = 0.26, P FDR = 2.23 x 10-8). PTSD showed significant genetic correlation with 11 other medication use traits including beta blocking agents (rG = -0.11, P FDR = 0.034). Of the 2495 genomic regions tested, PTSD showed significant local genetic correlation with 12 medication use traits at 43 loci; while migraine showed significant genetic correlation with only anti-inflammatory agents and anti-rheumatic products at locus 12:57522282-57607142 (DAB1) (P < 2 x 10-5). The genetic liability to PTSD had a causal effect on increased risk of using pain medication such as opioids (β ivw = 0.59, P = 5.21 x 10-5) while the genetic liability to migraine had a causal effect on the increased risk of using anti-thrombotic agents (β ivw = 0.59, P = 1.69 x 10-7). The genes in the genomic regions shared between PTSD and medication use traits were enriched in neural-related pathways such as neuron development, neurogenesis and protein kinase activity. These results provide further insight into the genetically controlled biological and environmental factors underlying the shared etiology between PTSD and migraine. The identified biomarkers can be used as a basis for investigation as potential drug targets for both disorders. These findings are significant for drug re-purposing and treatment of PTSD and migraine using monotherapy.

GWAS↗

PubMed2004

Clinical manifestations of genetic instability overlap one another.

Cancer syndromes are characteristic associations of specific malignancies with various congenital anomalies. In addition to such diseases, an increased prevalence in general of chromosomal instability, malformations, immunodeficiencies, altered growth and development, and reproductive loss has been observed in both childhood leukemias and solid tumors. The overlap among these congenital disorders suggests their common prenatal, possibly genetic origin and thus the existence of a nonspecific genetic instability leading to various clinical manifestations of disturbances in cell division. Seeking for related features in family members of a patient with malignancy may be of clinical value in detecting predisposition to cancer.

Animals↗

PubMed1985

The amino terminal half of the MS2-coded lysis protein is dispensable for function: implications for our understanding of coding region overlaps.

We have asked whether genetic overlaps only evolve to provide extra coding capacity in genomes of restricted size. As a model system we have used the lysis gene of the RNA bacteriophage MS2. This gene overlaps with the distal part of the coat protein gene and with the proximal part of the replicase gene. Using recombinant DNA procedures we have determined whether either of the two overlaps codes for amino acids that are not essential for the function of the 75 amino acid long lysis protein. We find that the first 40 amino acids of the lysis protein are dispensable for function. Thus all of the genetic information essential to the synthesis of the active C-terminal peptide lies within the overlap with the replicase gene, whereas all dispensable residues are encoded in the overlap with the coat protein gene and in the intercistronic region. This suggests that the overlap with the coat protein gene is not required for extra coding capacity but serves to regulate the expression of the lysis gene. Comparative sequence analysis is consistent with this idea.

Amino Acid Sequence↗

PubMed2003

A twin study of anxiety-related behaviours in pre-school children.

BACKGROUND: From middle childhood onwards, substantial evidence points to phenotypic differentiation between anxiety diagnostic categories such as generalised anxiety, separation anxiety, specific phobia, and obsessive-compulsive disorders. However, little is known about the genetics of these categories and especially about the phenotypic and genetic structure of related behaviours in pre-school children. METHODS: We examined the phenotypic differentiation and genetics of mother-reported anxiety-related behaviours in 4,564 four-year-old twin pairs, from a population-based sample. RESULTS: Confirmatory factor analyses provided support for five correlated factors: General Distress, Separation Anxiety, Fears, Obsessive-Compulsive Behaviours, and Shyness/Inhibition. Genetic influences were found on all five factors, but the pattern of influences differed considerably across them, with particularly high heritability estimates for Obsessive-Compulsive Behaviours and Shyness/Inhibition, and substantial shared environmental influence on Separation Anxiety. Multivariate genetic analyses revealed moderate genetic correlations between the five factors. Genetic overlap was particularly pronounced between General Distress and the other anxiety-related behaviours, accounting for about half of their covariance. Genetic variance on Obsessive-Compulsive Behaviours was the least correlated with the other scales. The shared environmental influences correlated highly across the factors, accounting for the greatest proportion of covariation between Separation Anxiety, Fears and Obsessive-Compulsive Behaviours. The non-shared environment influences were largely variable specific. CONCLUSIONS: These data provide evidence for phenotypic and genetic overlap as well as differentiation between aspects of anxiety-related behaviours in young children. We conclude that research with young children will benefit from more specific assessments of anxiety-related behaviours in addition to less differentiated assessments of 'internalising' symptoms.

Anxiety Disorders↗

PubMed2005

Topogenesis of peroxisomal proteins does not require a functional cytoplasm-to-vacuole transport.

Folded and even oligomeric proteins can be imported from the cytosol into vacuoles and into peroxisomes. Pro-aminopeptidase I (prAPI) oligomerizes into a dodecamer and is imported into the vacuole via the cytoplasm-to-vacuole transport (cvt) pathway. How peroxisomes accommodate folded proteins is completely unknown. Peroxisome biogenesis and cvt do not only share the import of folded protein complexes but also show mechanistic parallels such as the employment of ubiquitin conjugation systems. In search for a genetic overlap, selected cvt and autophagocytosis (atg) mutants were tested for defects in peroxisome biogenesis. Most of the mutants did not exhibit a mislocalization of peroxisomal matrix proteins to the cytosol which would be typical of a defect in the peroxisome biogenesis. However, two mutants, deltaatg14 and deltacvt4/vam6, displayed a general growth defect and deltacvt8/vps41 showed cytosolic mislocalization not only of peroxisomal but also of mitochondrial proteins, indicating a more general defect in organelle biogenesis. Our data do not provide evidence for a genetic overlap of the import pathway for peroxisomal proteins and the cvt pathway.

Autophagy↗

PubMed2004

Do aggressive and non-aggressive antisocial behaviors in adolescents result from the same genetic and environmental effects?

Antisocial behavior (ASB) in adolescents can broadly be separated into two forms; aggressive and non-aggressive. Both are heritable and it has been suggested that aggressive ASB is more heritable. The extent to which genes contribute to the correlation between the two is unknown. Structural equation modeling was applied to a population-based twin sample of 258 twins pairs aged 11-18 to estimate the heritability of each form of ASB and to estimate the extent to which the phenotypic correlation was the consequence of shared genes and environmental factors. Non-shared environment and genetic factors substantially influenced both forms of ASB. The heritability of aggressive (but not non-aggressive) ASB was significantly higher in girls than in boys. Combining both sexes, a model in which the genetic effects on aggressive and non-aggressive ASB were identical could be rejected. Our results suggest a partial genetic overlap with a specific genetic effect contributing to the variance of aggressive ASB and a stronger genetic effect on aggression in females than in males.

Adolescent↗

PubMed1976

Large overlapping tandem genetic duplications in Salmonella typhimurium.

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Alleles↗

PubMed2003

Familial aggregation of delusional proneness in schizophrenia and bipolar pedigrees.

OBJECTIVE: Clinical, familial, and, more recently, genetic linkage studies suggest that overlapping genetic susceptibility might contribute to both schizophrenia and bipolar disorder. To identify a potential psychotic dimension common to families of both bipolar and schizophrenia probands, the authors tested if delusional proneness was observed among first-degree relatives of bipolar and schizophrenia probands. METHOD: The authors included 32 schizophrenia probands and 61 bipolar probands and their respective first-degree relatives (N=63 and N=59). They were all interviewed with the Diagnostic Interview for Genetic Studies, and delusional proneness was assessed with a self-report questionnaire, the Peters et al. Delusions Inventory. Schizophrenia and bipolar probands were subdivided into subgroups according to the intensity of delusional symptoms assessed by Peters et al. Delusions Inventory scores, and the authors compared delusional proneness in their respective first-degree relatives. RESULTS: Familial aggregation of delusional proneness was demonstrated, since Peters et al. Delusions Inventory scores were higher among nonschizophrenic first-degree relatives of schizophrenia probands with productive symptoms and among first-degree relatives of bipolar probands with psychotic features during their affective episodes. The authors also found an intrafamilial correlation of delusional proneness scores in nonaffected siblings of schizophrenia and bipolar probands. CONCLUSIONS: Delusional proneness appears to be an inherited predisposition common to both schizophrenia and bipolar disorder. In the future, this dimension might be valuable when used as a quantitative phenotype in linkage and association studies.

Adult↗

PubMed1999

Genetic trends and breed overlap derived from multiple-breed genetic evaluations of beef cattle for growth traits.

Genetic evaluations for a multiple-breed population of beef cattle were used to estimate genetic trends for five breeds, and genetic differences and overlap among 14 breeds. Genetic evaluations studied were for direct contributions to birth weight, gain from birth to 200 and 365 d, and maternal contribution to gain from birth to 200 d. Almost all genetic trends were positive, but the magnitude of the trends varied among breeds. Trends were nonlinear between 1985 and 1995 for most breed and trait combinations. The rates of increase in genetic trends were generally higher for the lighter weight breeds, and lighter weight breeds had faster growth rate genetic trends at 1995 than the heavier breeds. Genetic trend estimates for yearling gain at 1995 were 2.46, 2.23, 1.73, 1.70, and 1.46 kg/yr for Angus, Hereford, Limousin, Charolais, and Simmental, respectively. Corresponding birth weight genetic trends were .130, .226, .049, .130, and .048 kg/yr. Mean genetic differences between breeds have been decreasing in magnitude due to these differences in genetic trends between heavier and lighter breeds. Genetic variation for the traits studied seemed to be greater within than between breeds for calves born and cows calving between 1993 and 1995. Genetic trends at 1995 suggest that ratios of within:between breed variation will increase and that across-breed genetic improvement initiatives for growth traits will become more important in the future.

Animals↗

PubMed1996

Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway.

We have explored the phenotypic and genetic overlap between autophagocytosis and cytoplasm to vacuole targeting in the yeast Saccharomyces cerevisiae. Complementation analysis was performed with mutants in each of these groups (aut and cvt, respectively), and three complementation groups were found to overlap. Also, most of the unique aut mutants accumulated precursor aminopeptidase I in the cytoplasm, while maintaining wild type kinetics and maturation of proteins targeted to the vacuole via the secretory pathway. The majority of the non-overlapping cvt mutants were found to be at least partially defective in autophagy. Some mutants in each group, however, appear to be only marginally affected in the other phenotype, implying that these pathways only partially overlap. We propose that import of aminopeptidase I into the vacuole shares a number of components required for bulk autophagocytosis, but is made specific, saturable, and constitutive by the presence of a receptor or other interacting protein(s).

Amino Acid Sequence↗

PubMed2006

A genome-wide search for quantitative trait loci contributing to variation in seasonal pollen reactivity.

BACKGROUND: Asthma and atopy represent complex traits for which genetic predisposition has been demonstrated. Pollen sensitivity, whether seasonal or chronic, appears to be a major contributor to the asthmatic phenotype. OBJECTIVE: Regions of the genome contributing to skin test reactivity to 5 seasonal allergens are to be identified in a genome-wide scan. These regions may be distinct from those contributing to risk for asthma and/or atopy. METHODS: In the Collaborative Study on the Genetics of Asthma, 4 sites collected 287 families with 2 or more members with asthma. Reactivity to individual pollens were determined on all family members. A genome scan was performed at 9-centiMorgan intervals, and skin test reactivity to 5 seasonal allergens was the focus of nonparametric genetic linkage analysis. RESULTS: Chromosomal regions that exhibited suggestive linkage (logarithm of the odds >1.18; P < .01) to seasonal pollen reactivity were identified on chromosomes 13q34, 20p12, and 21q21. Evidence of ethnic differences in linkage to seasonal allergens was demonstrated, with support for linkage in African American subjects on chromosomes 8, 10, and 12, in European American subjects on chromosomes 14, 19, 20, and 22, and in Hispanics on chromosome 21. In all families, evidence for linkage of skin test reactivity for Betula, Lolium, and Artemisia was strongest in a region on chromosome 21 that contained the candidate gene, A Disintegrin And Metalloprotease domain 33 (ADAM33). CONCLUSION: These results suggest both substantial genetic overlap and extensive heterogeneity in the genetic basis for the allergic response to seasonal allergens.

Adolescent↗

PubMed2001

Complete form of X-linked congenital stationary night blindness: refined mapping and evidence of genetic homogeneity.

A number of distinct, partly non-overlapping genetic loci have been reported for the complete type of X-linked congenital stationary night blindness (CSNB1), suggesting genetic heterogeneity. In order to refine the localization of the CSNB1 gene and to demonstrate genetic homogeneity, linkage analysis was performed in two large CSNB1 families. Clinical features consistent with the diagnosis of CSNB1 were documented in five patients from a German seven-generation kindred by full ophthalmological examination including psychophysical and electroretinographical testing. Haplotype analysis in 30 members of the large German family was performed with 38 polymorphic markers predominantly covering the critical region. Linkage analyses defined a locus for CSNB1 with flanking markers DXS8042 and DXS228, refining the interval to 2.5 cM in Xp11.4. In addition, two-point linkage analysis was carried out using the MLINK computer program. In agreement with meiotic breakpoints, lod scores of 3.0 and greater were obtained for markers located to the proximal site of the former 5 cM CSNB consensus interval. A large Dutch CSNB1 family was re-evaluated with markers from the Xp11.4 region, and supports the CSNB1 minimal interval found in the German family. Together with previous results from three unrelated families from Sweden, Sardinia and Great Britain, our results provide evidence of genetic homogeneity in the disorder. Subsequent mutation analyses in CSNB1 patients revealed no pathogenic sequence alterations in DFFRX and CASK genes, but retain candidates for other diseases mapping to that region.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2005

Refactoring bacteriophage T7.

Natural biological systems are selected by evolution to continue to exist and evolve. Evolution likely gives rise to complicated systems that are difficult to understand and manipulate. Here, we redesign the genome of a natural biological system, bacteriophage T7, in order to specify an engineered surrogate that, if viable, would be easier to study and extend. Our initial design goals were to physically separate and enable unique manipulation of primary genetic elements. Implicit in our design are the hypotheses that overlapping genetic elements are, in aggregate, nonessential for T7 viability and that our models for the functions encoded by elements are sufficient. To test our initial design, we replaced the left 11,515 base pairs (bp) of the 39,937 bp wild-type genome with 12,179 bp of engineered DNA. The resulting chimeric genome encodes a viable bacteriophage that appears to maintain key features of the original while being simpler to model and easier to manipulate. The viability of our initial design suggests that the genomes encoding natural biological systems can be systematically redesigned and built anew in service of scientific understanding or human intention.

Algorithms↗

PubMed2006

Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample.

Results from twin studies suggest that overlapping genetic factors influence alcohol dependence and illicit drug dependence. Using data from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined the association between 69 SNPs in the GABAA receptor gene cluster on chromosome 4 and marijuana and illicit drug dependence, individually, and as co-occurring phenotypes with alcohol dependence. Results suggested association between marijuana dependence and illicit drug dependence with SNPs in the GABRA2 gene. Interestingly, the evidence for association previously observed with alcohol dependence came only from individuals with comorbid illicit drug dependence. There was no association with other genes in the GABAA cluster on chromosome 4 with illicit drug dependence.

Alcoholism↗

PubMed2005

The genetic relationship between individual differences in social and nonsocial behaviours characteristic of autism.

Two types of behaviours shown in children - those reflecting social impairment and nonsocial obsessive repetitive behaviours - are central to defining and diagnosing autism spectrum disorders (ASDs). Parent and teacher data on social and nonsocial behaviours were obtained from a community sample of >3000 7-year-old twin pairs. Social and nonsocial behaviours were only modestly correlated, and it was found that some individuals had extreme scores on either social or nonsocial scales but not both. Genetic model-fitting showed that social and nonsocial behaviours are both highly heritable, but their genetic overlap is modest, with most of the genetic influence being specific to either social or nonsocial behaviours. Considering these behaviours separately might help clarify gene-brain-behaviour pathways in future research.

Autistic Disorder↗

PubMed2006

Association of the dysbindin gene with bipolar affective disorder.

OBJECTIVE: In the study of bipolar affective disorder and schizophrenia, there is some evidence suggesting a phenotypic and genetic overlap between the two disorders. A possible link between bipolar affective disorder and schizophrenia remains arguable, however. The authors hypothesized that dysbindin, which is a probable susceptibility gene for schizophrenia, was associated with bipolar affective disorder and tested this hypothesis using a case-control design study. METHOD: Participants included 213 patients with bipolar I disorder and 197 comparison subjects. In each subject, 10 polymorphisms in the dysbindin gene were genotyped and assessed. RESULTS: Two polymorphisms showed individual genotypic association with bipolar I disorder. Multiple marker haplotypes were more strongly associated, with the rarer of the two common haplotypes being overrepresented in the patients with bipolar affective disorder. A similar finding was reported in patients with schizophrenia in a previous study. CONCLUSIONS: Findings suggest that the human dysbindin gene may play a role in the susceptibility to bipolar affective disorder, which underscores a potentially important area of etiological overlap with schizophrenia. The existence of shared genetic risk factors will, in time, lead to changes in the current nosology of major psychoses.

Bipolar Disorder↗

PubMed2026

Large-Scale Neuroimaging and Genetic Analyses of the Human Thalamus in Loneliness.

BACKGROUND: Although loneliness is prevalent and significantly impacts society globally, its neural and genetic bases remain poorly understood. The thalamus, which receives sensory information from the environment, may have a more significant role in social interactions than previously recognized. Here, we integrate neuroimaging and genetic approaches to characterize structural differences within the thalamus associated with loneliness. METHODS: We obtained thalamic nuclei volumes on brain scans from 45,834 individuals (age range: 45-82 years) in the UK Biobank and grouped them into 6 anatomical groups. We investigated effects of loneliness and social isolation using self-reported data. Then, we performed a genome-wide association study (GWAS) analysis on the genetic overlap between thalamic volumes and loneliness. RESULTS: The volumes of the whole thalamus and its medial, lateral, and posterior nuclei are significantly reduced in individuals with loneliness compared with those who do not feel lonely. Loneliness with frequent social contact is associated with smaller volumes, whereas social isolation without loneliness shows no such reduction in thalamus volumes. Leveraging data from GWASs on thalamic volumes (n = 30,114) and loneliness (n = 370,342) in the UK Biobank, we identified shared loci between thalamus structure and loneliness. CONCLUSIONS: Our findings support the emerging view that the thalamus plays important roles in social interactions and in the experience of loneliness.

Genetic architecture↗

PubMed2006

Genetic analyses of DSM-IV nicotine withdrawal in adult twins.

BACKGROUND: We examined whether there are genetic influences on nicotine withdrawal, and whether there are genetic factors specific to nicotine withdrawal, after controlling for factors responsible for risk of progression beyond experimentation with cigarettes and for quantity smoked (average number of cigarettes per day at peak lifetime use). METHOD: Epidemiologic and genetic analyses were conducted using telephone diagnostic interview data from young adult Australian twins reporting any cigarette use (3026 women, 2553 men; mean age 30 years). RESULTS: Genetic analysis of the eight symptoms of DSM-IV nicotine withdrawal suggests heritability is intermediate for most symptoms (26-43%), and similar in men and women. The exceptions were depressed mood upon withdrawal, which had stronger additive genetic influences in men (53%) compared to women (29%), and decreased heart rate, which had low heritability (9%). Although prevalence rates were substantially lower for DSM-IV nicotine withdrawal syndrome (15.9%), which requires impairment, than for the DSM-IV nicotine dependence withdrawal criterion (43.6%), heritability was similar for both measures: as high as 47%. Genetic modeling of smoking more than 1 or 2 cigarettes lifetime ('progression'), quantity smoked and nicotine withdrawal found significant genetic overlap across all three components of nicotine use/dependence (genetic correlations = 0.53-0.76). Controlling for factors associated with risk of cigarette smoking beyond experimentation and quantity smoked, evidence for genetic influences specific to nicotine withdrawal (up to 23% of total variance) remained. CONCLUSIONS: Our results suggest that at least some individuals become 'hooked' or progress in the smoking habit, in part, because of a vulnerability to nicotine withdrawal.

Adult↗