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PubMed2026

Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale intrinsic brain networks reflect shared or disorder-specific genetic influences remains poorly understood. Clarifying this distinction is essential for refining etiological models and improving diagnostic precision. METHODS: Genome-wide inferred statistics (GWIS) were applied to decompose the genetic architecture of SCZ and BD into shared and unique components. Using resting-state network (RSN) data from the UK Biobank, functional connectivity (FC) and structural connectivity (SC) were extracted as neuroimaging phenotypes. Causal inference approaches were subsequently employed to infer potential directional relationships between brain network connectivity and each disorder. RESULTS: Analyses revealed both common and distinct patterns of brain network connectivity associated with SCZ and BD. Notably, SC within the default mode network (DMN) exhibited opposing effects across the two disorders, suggesting divergent structural underpinnings despite clinical overlap. Additionally, SC within the limbic network (LN) and frontotemporal control network demonstrated potential causal relationships with both conditions, implicating these circuits astransdiagnostic neural substrates. CONCLUSION: These findings illuminate the shared and disorder-specific genetic and neural architecture underlying SCZ and BD. Integrating genome-wide genetic methods with large-scale neuroimaging data offers a powerful framework for disentangling psychiatric comorbidity and may inform more targeted diagnostic criteria and individualized treatment strategies.

Humans↗
PubMed2002

Sequence analysis of Potato leafroll virus isolates reveals genetic stability, major evolutionary events and differential selection pressure between overlapping reading frame products.

In order to investigate the genetic diversity of Potato leafroll virus (PLRV), seven new complete genomic sequences of isolates collected worldwide were compared with the five sequences available in GenBank. Then, a restricted polymorphic region of the genome was chosen to further analyse new sequences. The sequences of PLRV open reading frames (ORFs) 3 and 4 were also compared with those of two other poleroviruses and the non-synonymous to synonymous substitution ratio distribution was analysed in overlapping and non-overlapping regions of the genome using maximum-likelihood models. Results confirmed that PLRV sequences from around the world are very closely related and showed that the region encoding protein P0 allowed the detection of three groups of isolates. When compared to other poleroviruses, PLRV was the most conserved in both ORFs 3 and 4. However, the results suggest that important events, such as deletion, mutation at a stop codon and intraspecific homologous recombination events, have occurred during the evolution of PLRV. Finally, it was shown that the translation products of ORFs 0 and 3 are significantly more conserved than those of the overlapping ORFs 1 and 4, respectively. All together, the results allow the proposal of new hypotheses to explain the apparent genetic stability of PLRV and its evolution.

Biological Evolution↗
PubMed1994

Genetic analysis of Rough sheath1 developmental mutants of maize.

Maize Rough sheath1 (Rs1) mutants are dominant and cause a proliferation of sheath-like tissue at the base of the blade and throughout the ligular region. They also cause ligule displacement, a chaotic pattern of vasculature and abnormal cellular structure of vascular bundles. The affected region of Rs1-O leaves displays genetic and morphological attributes of both sheath and auricle, suggesting an overlap of these genetic programs. The rs1 locus maps approximately 26 map units distal to opaque2 (o2) on chromosome 7S, defining a new distal-most locus on the genetic map. Three mutant alleles, Rs1-O, Rs1-1025 and Rs1-Z, all display similar phenotypes. The mutations are completely dominant and the Rs1-O phenotype is not affected by dosage of the chromosome arm carrying the rs1+ allele, indicating that these alleles are neomorphic. Analysis of genetic mosaics showed that the Rs1-O phenotype is non-cell-autonomous, suggesting that intercellular signals convey the phenotype. Rs1 mutant phenotypes are affected by modifiers present in particular genetic backgrounds. An enhancer of Rs1-O was identified; segregation data imply a single recessive gene, ers1. Rs1 mutants were also found to enhance the expression of unlinked rs2 and Rs4 mutants, suggesting that these mutations affect similar developmental processes. We discuss the phenotypic and genetic similarities between Rs1 and Knotted 1 (Kn1) mutants that led to the identification of rs1 as a kn1-like homeobox gene (unpublished data).

Crosses, Genetic↗
PubMed2002

Chronic fatigue and anxiety/depression: a twin study.

BACKGROUND: Up to three-quarters of patients with fatigue syndromes have comorbid mood or anxiety disorders, suggesting that chronic fatigue is a forme fruste of anxiety or depressive states. AIMS: To establish whether the association of chronic fatigue with psychological distress is causal or due to a common genetic or environmental factor. METHOD: 69 monozygotic (MZ) and 31 dizygotic (DZ) female twin pairs, with only one co-twin reporting at least 6 months of fatigue, completed questions on fatigue, the General Health Questionnaire (GHQ) and a structured psychiatric interview. We examined the effects of three progressively more stringent definitions of chronic fatigue on four GHQ sub-scales. RESULTS: Fatigued MZ and DZ twins by all definitions were significantly more depressed, anxious, somatically preoccupied and socially dysfunctional than their non-fatigued co-twins. Intrapair differences were similar in DZ and MZ twins, but non-significant differences were observed for the somatic symptoms and anxiety/insomnia sub-scales. CONCLUSIONS: In this sample, chronic fatigue and psychological distress are strongly associated without evidence for genetic covariation, implying that the association is environmental, or due to overlapping definitions. Any genetic covariation missed is likely to involve anxiety rather than depression.

Adult↗
PubMed1988

Genomic organization of major sperm protein genes and pseudogenes in the nematode Caenorhabditis elegans.

The major sperm proteins (MSPs) are a family of closely related, small, basic proteins comprising 15% of the protein in Caenorhabditis elegans sperm. They are encoded by a multigene family of more than 50 genes, including many pseudogenes. MSP gene transcription occurs only in late primary spermatocytes. In order to study the genomic organization of transcribed MSP genes, probes specific for the 3' untranslated regions of sequenced cDNA clones were used to isolate transcribed genes from genomic libraries. These and other clones of MSP genes were located in overlapping cosmid clones by DNA fingerprinting. These cosmids were aligned with the genetic map by overlap with known genes or in-situ hybridization to chromosomes. Of 40 MSP genes identified, 37, including all those known to be transcribed, are organized into six clusters composed of 3 to 13 genes each. Within each cluster, MSP genes are not in tandem but are separated by at least several thousand bases of DNA. Pseudogenes are interspersed among functional genes. Genes with similar 3' untranslated sequences are in the same cluster. The six MSP clusters are confined to only three chromosomal loci; one on the left arm of chromosome II and two near the middle of chromosome IV. Additional sperm-specific genes are located in one cluster of MSP genes on chromosome IV. The multiplicity of MSP genes appears to be a mechanism for enhancing MSP synthesis in spermatocytes, and the loose clustering of genes could be a result of the mechanism of gene duplication or could play a role in regulation.

Animals↗
PubMed2004

Combining biological networks to predict genetic interactions.

Genetic interactions define overlapping functions and compensatory pathways. In particular, synthetic sick or lethal (SSL) genetic interactions are important for understanding how an organism tolerates random mutation, i.e., genetic robustness. Comprehensive identification of SSL relationships remains far from complete in any organism, because mapping these networks is highly labor intensive. The ability to predict SSL interactions, however, could efficiently guide further SSL discovery. Toward this end, we predicted pairs of SSL genes in Saccharomyces cerevisiae by using probabilistic decision trees to integrate multiple types of data, including localization, mRNA expression, physical interaction, protein function, and characteristics of network topology. Experimental evidence demonstrated the reliability of this strategy, which, when extended to human SSL interactions, may prove valuable in discovering drug targets for cancer therapy and in identifying genes responsible for multigenic diseases.

Animals↗
PubMed2004

Gaps, inexperience, inconsistencies, and overlaps: crisis in the regulation of genetically modified plants and animals.

The regulation of genetically modified products pursuant to statutes enacted decades prior to the advent of biotechnology has created a regulatory system that is passive rather than proactive about risks, has difficulty adapting to biotechnology advances, and is highly fractured and inefficient--transgenic plants and animals are governed by at least twelve different statutes and five different agencies or services. The deficiencies resulting from this piecemeal approach to regulation unnecessarily expose society and the environment to adverse risks of biotechnology and introduce numerous inefficiencies into the regulatory system. These risks and inefficiencies include gaps in regulation, duplicative and inconsistent regulation, unnecessary increases in the cost of and delay in the development and commercialization of new biotechnology products. These deficiencies also increase the risk of further unnecessary biotechnology scares, which may cause public overreaction against biotechnology products, preventing the maximization of social welfare. With science and society poised to soar from first-generation biotechnology (focused on crops modified for agricultural benefit), to next-generation developments (including transgenic fish, insects, and livestock, and pharmaceutical-producing and industrial compound-producing plants and animals), it is necessary to establish a comprehensive, efficient, and scientifically rigorous regulatory system. This Article details how to achieve such a result through fixing the deficiencies in, and risks created by, the current regulatory structure. Ignoring many details, the solutions can be summarized in two categories. First, statutory and regulatory gaps that are identified must be closed with new legislation and regulation. Second, regulation of genetically modified products must be shifted from a haphazard model based on statutes not intended to cover biotechnology to a system based upon agency expertise in handling particular types of risks.

Animals↗
PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗
PubMed2006

Noonan syndrome and related disorders: alterations in growth and puberty.

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548-555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465-468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652-662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413-427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42-48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038-1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet, 2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294-296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis.

Abnormalities, Multiple↗
PubMed2005

Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.

Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.

Adolescent↗
PubMed2005

Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes?

Schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies.

Bipolar Disorder↗
PubMed2003

Pick Complex: an integrative approach to frontotemporal dementia: primary progressive aphasia, corticobasal degeneration, and progressive supranuclear palsy.

BACKGROUND: Frontotemporal dementia (FTD) is a new label for clinical Pick's disease (PiD) because the eponymic term is increasingly restricted to the pathologic finding of Pick bodies. This restriction created the impression that PiD is rare and that is it difficult to diagnose. FTD is also a term most often used for behavioral and personality alterations. Primary progressive aphasia (PPA) and corticobasal degeneration (CBD), formerly the extrapyramidal variety of PiD, are also part of the syndrome. Recently, chromosome 17 localization and tau mutations were discovered in familial forms of the disease. REVIEW SUMMARY: FTD consists of behavioral and personality changes, often beginning with apathy and disinterest, which may be mistaken for depression. Disinhibition and perseverative, compulsive behavior often appear at the same time. A quantifiable frontal behavioral inventory is useful in the diagnosis beyond a checklist. The second type of presentation is progressive language loss (PPA). A less common variety is semantic dementia: the meaning of nouns and objects is lost. As the disease progresses, all components tend to overlap. CBD and progressive supranuclear palsy (PSP), although described as distinct entities, show a great deal of clinical, pathologic, genetic, and biochemical overlap. The evidence suggests they also belong to the complex. The association of motor neuron disease (MND) with FTD and other varieties of the complex is also reviewed. CONCLUSIONS: Clinical Pick's disease or Pick Complex includes the overlapping syndromes of FTD, PPA, CBD, PSP, and FTD-MND. The neuropathological and genetic spectrum should be viewed with emphasis on the commonalities rather than the differences, allowing the recognition of the relatively high frequency of this presenile syndrome.

Aphasia, Primary Progressive↗
PubMed2001

Hypermethylation of the promoter region of the E-cadherin gene (CDH1) in sporadic and ulcerative colitis associated colorectal cancer.

BACKGROUND: Ulcerative colitis associated colorectal cancer (UCACRC) has several distinctive clinicopathological and genetic features which differ from sporadic colorectal cancer (SCRC). Hypermethylation of the E-cadherin gene (CDH1) has not been described previously in colorectal cancer. AIMS: A panel of SCRC and UCACRC were investigated for mutations in CDH1, and for hypermethylation of the promoter region of CDH1. SUBJECTS AND METHODS: DNA was available from 14 patients with UCACRC and from 14 with SCRC. All exons of CDH1 were amplified with the polymerase chain reaction (PCR) and screened using single strand conformational polymorphism and direct sequencing. Hypermethylation of the CDH1 promoter region was determined by methylation specific PCR following bisulphite modification, and compared with E-cadherin protein expression from a previous immunohistochemistry study. RESULTS: Thirteen of 28 cancers (46%) were hypermethylated in the CDH1 promoter region-eight cancers (57%) in the UCACRC group and five cancers (36%) in the SCRC group (NS)-and this correlated with reduced E-cadherin expression (p<0.05). There was a trend for methylation to be associated with a more advanced stage of cancer although this did not reach statistical significance. There were no mutations in CDH1 in either group although there were several polymorphisms. CONCLUSION: We have demonstrated hypermethylation of the promoter region in CDH1 in 46% of colorectal cancers studied. There was no difference between the UCACRC and SCRC groups. Just as there are specific differences in the genetic changes between UCACRC and SCRC, there is also likely to be a large degree of overlap among the genetic pathways of these cancers.

Cadherins↗
PubMed1976

Convergence of genetic compositions assuming infinite population-size and overlapping generations.

The assumptions for the model treated in this paper are based on a population of hypothetically infinite size, which has reached its optimum density within a limited habitat. The aim has been to derive sufficient conditions for the genetic composition of a population to converge to a limit if generations overlap and time is measured in discrete intervals. Trivially the genetic composition does not change if at the starting point of time the compositions within all age-classes are the same; otherwise global convergence of the age-class distributions implies uniform convergence of the genetic compositions within the single age-classes if mating takes place between at least two age-classes, or within the first age-class only. Excluding age-class 1 mating within one age-class only results in periodical change of genetic compositions.

Age Factors↗
PubMed2003

GALA, a database for genomic sequence alignments and annotations.

We have developed a relational database to contain whole genome sequence alignments between human and mouse with extensive annotations of the human sequence. Complex queries are supported on recorded features, both directly and on proximity among them. Searches can reveal a wide variety of relationships, such as finding all genes expressed in a designated tissue that have a highly conserved noncoding sequence 5' to the start site. Other examples are finding single nucleotide polymorphisms that occur in conserved noncoding regions upstream of genes and identifying CpG islands that overlap the 5' ends of divergently transcribed genes. The database is available online at http://globin.cse.psu.edu/ and http://bio.cse.psu.edu/.

5' Untranslated Regions↗
PubMed2000

The relation between risk factors for binge eating and bulimia nervosa: a population-based female twin study.

This study investigated the differential risk factors for the initiation of binge eating and the transition from binge eating to bulimia nervosa. Women from a population-based twin registry (850 complete pairs) were assessed with respect to specific measured variables (including demographics, religiosity, lifetime psychopathology, current symptomatology, and personality) and latent genetic and environmental variables. Because of the relative rarity of bulimia nervosa, statistical power was low, but findings suggested considerable overlap between the genetic risk factors for the development of binge eating and the genetic risk factors for the transition from binge eating to bulimia nervosa. Genetic risk factors for binge eating and bulimia nervosa may be largely similar, whereas nonshared environment may be important in influencing the risk for bulimia nervosa once binge eating is initiated.

Adult↗
PubMed2006

A population-based twin study of the relationship between neuroticism and internalizing disorders.

OBJECTIVE: The anxiety and depressive disorders exhibit high levels of lifetime comorbidity with one another. The authors examined how genetic and environmental factors shared by the personality trait neuroticism and seven internalizing disorders may help explain this comorbidity. METHOD: Lifetime major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, situational phobia, and neuroticism were assessed in over 9,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Multivariate structural equation models were used to decompose the correlations between these phenotypes into genetic and environmental components, allowing for sex-specific factors. RESULTS: Genetic factors shared with neuroticism accounted for between one-third and one-half of the genetic risk across the internalizing disorders. When nonsignificant gender differences were removed from the models, the genetic correlations between neuroticism and each disorder were high, while individual-specific environmental correlations were substantially lower. In addition, the authors could identify a neuroticism-independent genetic factor that significantly increased risk for major depression, generalized anxiety disorder, and panic disorder. CONCLUSIONS: There is substantial, but not complete, overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability across the internalizing disorders, helping to explain the high rates of comorbidity among the latter. This may have important implications for identifying the susceptibility genes for these conditions.

Adult↗