The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

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

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

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

Meiose e viabilidade polínica na família Araceae Meiosis and pollen viability in Araceae family

O objetivo deste trabalho foi analisar a microsporogênese e a viabilidade dos grãos de pólen em 17 espécies de aráceas coletadas no Rio Grande do Sul, Brasil. Nove espécies foram analisadas quanto à ocorrência de células mãe de pólen (CMP) normais e anormais nas fases de metáfase, anáfase e telófase, tanto da meiose I (M I) como da meiose II (M II); 10 espécies foram estudadas quanto à presença de tétrades com número normal ou anormal de micrósporos e 17 espécies quanto à viabilidade dos grãos de pólen. As CMP anormais apresentaram, tanto em M I quanto em M II, cromossomos fora da placa metafásica ou cromossomos retardatários em anáfase e/ou telófase. As freqüências de CMP normais/anormais encontradas na microsporogênese salientam a grande variação existente entre as espécies. Ressalta-se a ausência de CMP com anomalias na microsporogênese de Monstera deliciosa Adans., assim como em M I de Anthurium scandens (Aubl) Engl. e em M II de Caladium hortulanum Birdsey. O número observado de CMP anômalas, em M I e M II, nas espécies Syngonium podophyllum Schott e Zantedeschia aethiopica Spreng, foi maior que o esperado. A freqüência média de tétrades normais em dez espécies de aráceas, assim como a de grãos de pólen viáveis em 17 espécies, foi significativamente superior à freqüência média de anormais e de inviáveis, respectivamente.<br>The objective of this work was to analyze microsporogenesis and pollen viability in 17 species of the Araceae family collected at Rio Grande do Sul, Brazil. Occurrence of normal and abnormal pollen mother cells (PMC) was analyzed in metaphase, anaphase and telophase, in meiosis I (M I) and meiosis II (M II) of nine species; tetrads with normal or abnormal number of microspores was observed in 10 species, and pollen grain viability, in 17 species. Abnormal PMC presented chromosomes outside the metaphasic plate or laggard chromosomes in anaphase and/or telophase in both M I and M II. The frequencies of normal/abnormal PMC found in microsporogenesis point out to the existence of great variation among the species. It should be emphasized the absence of PMC with abnormalities in Monstera deliciosa Adans. microsporogenesis, as well as in Anthurium scandens (Aubl) Engl. M I and in Caladium hortulanum Birdsey M II. The number of anomalous PMC in Syngonium podophyllum Schott and Zantedeschia aethiopica Spreng in M I and M IIwas higher than expected. Average frequency of normal tetrads in ten araceous species and viable pollen grains in 17 species were significantly superior to the average frequency of abnormal tetrads and unviable pollen grains, respectively