The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Background: Alzheimer's disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer's Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR=0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR=0.022, opposite direction of effect). Conclusions: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Gratte-ciel, cascades d'eau, rues, ruisseaux ... une construction

Water channel, detail; In the 1980s the city of Montreal announced its intention to transform the block into the Place du 350e, a square to commemorate the 350th anniversary of the founding of Montreal. An architectural competition to redesign the square was won by Melvin Charney, the internationally acclaimed, Montreal-based architect and artist whose works include a highly regarded garden on the site of the Canadian Centre for Architecture. Charney's redesign of the square included a multi-formed sculpture, 'Gratte-ciel, cascades d'eau, rues, ruisseaux ... une construction' (Skyscraper, Waterfall, Roads, Brooks … a Construction), which expressed the larger logic with which he had reimagined the square. Source: Global Cities/Local Sites [ebook by Straw, Will and DouglasTallack]; http://strawresearch.mcgill.ca/straw/ThreeblocksinMontreal.pdf (accessed 7/12/2010

CCA Sculpture Garden

View into the "colonnes allegoriques"; The CCA Garden restores the urban fabric of an area deeply scarred by mid-20th-century highway engineering. Initiated as part of the Québec government's program for the integration of art and architecture into the landscape, the garden faces the CCA from the south side of boulevard René-Lévesque. This site was granted to the CCA by the City of Montréal in 1986, and the design by Montréal artist-architect Melvin Charney integrates sculpture and public space with remarkable results. At once a garden in the city and a museum in the open air, it evokes the richly diverse history of landscape design and initiates a dialogue between nature, architecture, and the urban fabric. The garden is laid out as a series of narrative episodes - Orchard, Meadow, Arcade (mirror of the Shaughnessy House), Esplanade, Belvedere, and Allegorical Columns - each of which relates to the wider history of architecture as well as to the city that surrounds the site. Source: Canadian Centre for Architecture; http://www.cca.qc.ca (accessed 2/8/2008

CCA Sculpture Garden

A "colonne allegorique"; The CCA Garden restores the urban fabric of an area deeply scarred by mid-20th-century highway engineering. Initiated as part of the Québec government's program for the integration of art and architecture into the landscape, the garden faces the CCA from the south side of boulevard René-Lévesque. This site was granted to the CCA by the City of Montréal in 1986, and the design by Montréal artist-architect Melvin Charney integrates sculpture and public space with remarkable results. At once a garden in the city and a museum in the open air, it evokes the richly diverse history of landscape design and initiates a dialogue between nature, architecture, and the urban fabric. The garden is laid out as a series of narrative episodes - Orchard, Meadow, Arcade (mirror of the Shaughnessy House), Esplanade, Belvedere, and Allegorical Columns - each of which relates to the wider history of architecture as well as to the city that surrounds the site. Source: Canadian Centre for Architecture; http://www.cca.qc.ca (accessed 2/8/2008

Gratte-ciel, cascades d'eau, rues, ruisseaux ... une construction

Steel tower, detail; In the 1980s the city of Montreal announced its intention to transform the block into the Place du 350e, a square to commemorate the 350th anniversary of the founding of Montreal. An architectural competition to redesign the square was won by Melvin Charney, the internationally acclaimed, Montreal-based architect and artist whose works include a highly regarded garden on the site of the Canadian Centre for Architecture. Charney's redesign of the square included a multi-formed sculpture, 'Gratte-ciel, cascades d'eau, rues, ruisseaux ... une construction' (Skyscraper, Waterfall, Roads, Brooks … a Construction), which expressed the larger logic with which he had reimagined the square. Source: Global Cities/Local Sites [ebook by Straw, Will and DouglasTallack]; http://strawresearch.mcgill.ca/straw/ThreeblocksinMontreal.pdf (accessed 7/12/2010

CCA Sculpture Garden

A "colonne allegorique"; The CCA Garden restores the urban fabric of an area deeply scarred by mid-20th-century highway engineering. Initiated as part of the Québec government's program for the integration of art and architecture into the landscape, the garden faces the CCA from the south side of boulevard René-Lévesque. This site was granted to the CCA by the City of Montréal in 1986, and the design by Montréal artist-architect Melvin Charney integrates sculpture and public space with remarkable results. At once a garden in the city and a museum in the open air, it evokes the richly diverse history of landscape design and initiates a dialogue between nature, architecture, and the urban fabric. The garden is laid out as a series of narrative episodes - Orchard, Meadow, Arcade (mirror of the Shaughnessy House), Esplanade, Belvedere, and Allegorical Columns - each of which relates to the wider history of architecture as well as to the city that surrounds the site. Source: Canadian Centre for Architecture; http://www.cca.qc.ca (accessed 2/8/2008