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Journal of Affective Disorders Jul 2018Identifying the phenotypic manifestations of increased genetic liability for depression (MDD) and bipolar disorder (BD) can enhance understanding of their aetiology. The... (Review)
Review
BACKGROUND
Identifying the phenotypic manifestations of increased genetic liability for depression (MDD) and bipolar disorder (BD) can enhance understanding of their aetiology. The polygenic risk score (PRS) derived using data from genome-wide-association-studies can be used to explore how genetic risk is manifest in different samples.
AIMS
In this systematic review, we review studies that examine associations between the MDD and BD polygenic risk scores and phenotypic outcomes.
METHODS
Following PRISMA guidelines, we searched EMBASE, Medline and PsycINFO (from August 2009 - 14th March 2016) and references of included studies. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate.
RESULTS
Twenty-five studies were included. Overall, both polygenic risk scores were associated with other psychiatric disorders (not the discovery sample disorder) such as depression, schizophrenia and bipolar disorder, greater symptom severity of depression, membership of a creative profession and greater educational attainment. Both depression and bipolar polygenic risk scores explained small amounts of variance in most phenotypes (< 2%).
LIMITATIONS
Many studies did not report standardised effect sizes. This prevented us from conducting a meta-analysis.
CONCLUSIONS
Polygenic risk scores for BD and MDD are associated with a range of phenotypes and outcomes. However, they only explain a small amount of the variation in these phenotypes. Larger discovery and adequately powered target samples are required to increase power of the PRS approach. This could elucidate how genetic risk for bipolar disorder and depression is manifest and contribute meaningfully to stratified medicine.
Topics: Bipolar Disorder; Depression; Depressive Disorder, Major; Humans; Multifactorial Inheritance; Phenotype; Risk Factors; Schizophrenia
PubMed: 29529547
DOI: 10.1016/j.jad.2018.02.005 -
Schizophrenia Research Jul 2018Studying the phenotypic manifestations of increased genetic liability for schizophrenia can increase our understanding of this disorder. Specifically, information from...
Studying the phenotypic manifestations of increased genetic liability for schizophrenia can increase our understanding of this disorder. Specifically, information from alleles identified in genome-wide association studies can be collapsed into a polygenic risk score (PRS) to explore how genetic risk is manifest within different samples. In this systematic review, we provide a comprehensive assessment of studies examining associations between schizophrenia PRS (SZ-PRS) and several phenotypic measures. We searched EMBASE, Medline and PsycINFO (from August 2009-14th March 2016) plus references of included studies, following PRISMA guidelines. Study inclusion was based on predetermined criteria and data were extracted independently and in duplicate. Overall, SZ-PRS was associated with increased risk for psychiatric disorders such as depression and bipolar disorder, lower performance IQ and negative symptoms. SZ-PRS explained up to 6% of genetic variation in psychiatric phenotypes, compared to <0.7% in measures of cognition. Future gains from using the PRS approach may be greater if used for examining phenotypes that are more closely related to biological substrates, for scores based on gene-pathways, and where PRSs are used to stratify individuals for study of treatment response. As it was difficult to interpret findings across studies due to insufficient information provided by many studies, we propose a framework to guide robust reporting of PRS associations in the future.
Topics: Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype; Risk Assessment; Schizophrenia
PubMed: 29129507
DOI: 10.1016/j.schres.2017.10.037 -
The British Journal of Dermatology Oct 2017Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the... (Review)
Review
Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.
Topics: Genetic Predisposition to Disease; Genetic Variation; Genotype; Heterozygote; Hidradenitis Suppurativa; Humans; Mutation; Promoter Regions, Genetic; RNA Splice Sites; Receptors, Notch
PubMed: 28278367
DOI: 10.1111/bjd.15441