Genetic overlap between schizophrenia and bipolar disorder: A study with AKT1 gene variants and clinical phenotypes

Catechol-O-methyltransferase (COMT) has a central role in brain dopamine, noradrenalin and adrenalin signaling, and has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The functional single nucleotide polymorphism (SNP) in exon 4 (Val158Met, rs4680) influences the COMT enzyme activity. The Val158Met polymorphism is a commonly studied variant in psychiatric genetics, and initial studies in schizophrenia and bipolar disorder presented evidence for association with the Met allele. In unipolar depression, while some of the investigations point at an association between the Met/Met genotype and others have found a link between the Val/Val genotype and depression, most of the studies cannot detect any difference in Val158Met allele frequency between depressed individuals and controls.In the present study, we further elucidated the impact of COMT polymorphisms including the Val158Met in MDD. We investigated 1,250 subjects with DSM-IV and/or ICD-10 diagnosis of major depression (MDD), and 1,589 control subjects from UK. A total of 24 SNPs spanning the COMT gene were successfully genotyped using the Illumina HumaHap610-Quad Beadchip (22 SNPs), SNPlex™ genotyping system (1 SNP), and Sequenom MassARRAY® iPLEX Gold (1 SNP). Statistical analyses were implemented using PASW Statistics18, FINETTI (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), UNPHASED version 3.0.10 program and Haploview 4.0 program.Neither single-marker nor haplotypic association was found with the functional Val158Met polymorphism or with any of the other SNPs genotyped. Our findings do not provide evidence that COMT plays a role in MDD or that this gene explains part of the genetic overlap with bipolar disorder.

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Recent advances in the understanding and management of bipolar disorder in adults

F1000Research ◽

10.12688/f1000research.12329.1 ◽

2017 ◽

Vol 6 ◽

pp. 2033 ◽

Cited By ~ 8

Author(s):

Janusz K. Rybakowski

Keyword(s):

Bipolar Disorder ◽

Psychiatric Disorders ◽

Recent Progress ◽

Molecular Genetic ◽

Mood Stabilizer ◽

New Drugs ◽

Specific Drug ◽

Genetic Approach ◽

The Past ◽

Genetic Overlap

This article focuses on some aspects of recent progress in the neurobiology and treatment of bipolar disorder (BD) in adults. A molecular-genetic approach to the etiopathogenesis of the illness resulted in the findings of a genetic overlap between BD and other major psychiatric disorders. Furthermore, a poly-gene-environmental interaction in the development of the illness has been demonstrated. For the management of BD, new drugs with putative mood-stabilizing properties have been introduced in the past two decades. However, none of these can surpass lithium, the prototype mood-stabilizer, still considered the most specific drug for BD. Recent research on lithium, besides providing new data on the neurobiology of BD, has confirmed anti-suicidal, immunomodulatory, and neuroprotective properties of this drug.

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P.2.d.024 Lithium and GSK-3β promoter gene variants influence gray matter volume in bipolar disorder

European Neuropsychopharmacology ◽

10.1016/s0924-977x(14)70682-0 ◽

2014 ◽

Vol 24 ◽

pp. S427 ◽

Cited By ~ 1

Author(s):

S. Poletti ◽

C. Locatelli ◽

D. Radaelli ◽

C. Colombo ◽

F. Benedetti

Keyword(s):

Bipolar Disorder ◽

Gray Matter ◽

Gray Matter Volume ◽

Gene Variants ◽

Matter Volume ◽

Promoter Gene ◽

Gsk 3Β

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SA121GENOME-WIDE ANALYSIS REVEALS EXTENSIVE GENETIC OVERLAP BETWEEN SCHIZOPHRENIA, BIPOLAR DISORDER AND GENERAL COGNITIVE ABILITY

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2018.08.343 ◽

2019 ◽

Vol 29 ◽

pp. S1255

Author(s):

Olav Smeland ◽

Oleksandr Frei ◽

Shahram Bahrami ◽

Alexey Shadrin ◽

Torill Ueland ◽

...

Keyword(s):

Bipolar Disorder ◽

Cognitive Ability ◽

General Cognitive Ability ◽

Genetic Overlap

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No evidence for association between bipolar disorder risk gene variants and brain structural phenotypes

Journal of Affective Disorders ◽

10.1016/j.jad.2013.06.008 ◽

2013 ◽

Vol 151 (1) ◽

pp. 291-297 ◽

Cited By ~ 13

Author(s):

Martin Tesli ◽

Randi Egeland ◽

Ida E. Sønderby ◽

Unn K. Haukvik ◽

Francesco Bettella ◽

...

Keyword(s):

Bipolar Disorder ◽

Gene Variants ◽

Risk Gene ◽

Disorder Risk

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Gender-specific association of the SLC6A4 and DRD2 gene variants in bipolar disorder

The International Journal of Neuropsychopharmacology ◽

10.1017/s1461145713001296 ◽

2013 ◽

Vol 17 (02) ◽

pp. 211-222 ◽

Cited By ~ 12

Author(s):

Tzu-Yun Wang ◽

Sheng-Yu Lee ◽

Shiou-Lan Chen ◽

Yun-Hsuan Chang ◽

Shih-Heng Chen ◽

...

Keyword(s):

Bipolar Disorder ◽

Gene Variants ◽

Drd2 Gene ◽

Specific Association ◽

Gender Specific

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Multidimensional assessment of impulsivity in schizophrenia, bipolar disorder, and major depressive disorder: testing for shared endophenotypes

Psychological Medicine ◽

10.1017/s0033291716000131 ◽

2016 ◽

Vol 46 (7) ◽

pp. 1497-1507 ◽

Cited By ~ 21

Author(s):

R. G. Fortgang ◽

C. M. Hultman ◽

T. G. M. van Erp ◽

T. D. Cannon

Keyword(s):

Bipolar Disorder ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Sensation Seeking ◽

Behavioral Measure ◽

Clinical Feature ◽

Major Depressive ◽

Genetic Overlap ◽

Stop Signal Reaction Time ◽

Genetic Loading

BackgroundImpulsivity is associated with bipolar disorder as a clinical feature during and between manic episodes and is considered a potential endophenotype for the disorder. Schizophrenia and major depressive disorder share substantial genetic overlap with bipolar disorder, and these two disorders have also been associated with elevations in impulsivity. However, little is known about the degree of overlap among these disorders in discrete subfacets of impulsivity and whether any overlap is purely phenotypic or due to shared genetic diathesis.MethodWe focused on five subfacets of impulsivity: self-reported attentional, motor, and non-planning impulsivity, self-reported sensation seeking, and a behavioral measure of motor inhibition (stop signal reaction time; SSRT). We examined these facets within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic patterning in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420).ResultsWe found evidence of moderate to high levels of heritability for all five subfacets. All three proband groups and their unaffected co-twins showed elevations on attentional, motor, and non-planning impulsivity. Schizophrenia probands (but not their co-twins) showed significantly lower sensation seeking, and schizophrenia and bipolar disorder probands (but not in their co-twins) had significantly longer SSRTs, compared with healthy controls and the other groups.ConclusionsAttentional, motor, and non-planning impulsivity emerged as potential shared endophenotypes for the three disorders, whereas sensation seeking and SSRT were associated with phenotypic affection but not genetic loading for these disorders.

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Genome-wide analysis of adolescent psychotic experiences shows genetic overlap with psychiatric disorders

10.1101/265512 ◽

2018 ◽

Author(s):

Oliver Pain ◽

Frank Dudbridge ◽

Alastair G. Cardno ◽

Daniel Freeman ◽

Yi Lu ◽

...

Keyword(s):

Bipolar Disorder ◽

Major Depression ◽

Psychiatric Disorders ◽

Negative Symptoms ◽

Genome Wide Association Study ◽

Genetic Influences ◽

Psychotic Experiences ◽

Psychotic Experience ◽

Genome Wide ◽

Genetic Overlap

AbstractThis study aimed to test for overlap in genetic influences between psychotic experience traits shown by adolescents in the community, and clinically-recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297-10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic experience domain was performed. SNP-heritability of each psychotic experience domain was estimated using genomic-relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium-(LD-) score regression. Genetic overlap between specific psychotic experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk scoring (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent-rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically-recognized psychiatric disorders, specifically schizophrenia and major depression.

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