Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs ...that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.
We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.
Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.
Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.
With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By ...applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.
Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, ...several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements—well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms—to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.
Abstract
Inferring changes in effective population size (Ne) in the recent past is of special interest for conservation of endangered species and for human history research. Current methods for ...estimating the very recent historical Ne are unable to detect complex demographic trajectories involving multiple episodes of bottlenecks, drops, and expansions. We develop a theoretical and computational framework to infer the demographic history of a population within the past 100 generations from the observed spectrum of linkage disequilibrium (LD) of pairs of loci over a wide range of recombination rates in a sample of contemporary individuals. The cumulative contributions of all of the previous generations to the observed LD are included in our model, and a genetic algorithm is used to search for the sequence of historical Ne values that best explains the observed LD spectrum. The method can be applied from large samples to samples of fewer than ten individuals using a variety of genotyping and DNA sequencing data: haploid, diploid with phased or unphased genotypes and pseudohaploid data from low-coverage sequencing. The method was tested by computer simulation for sensitivity to genotyping errors, temporal heterogeneity of samples, population admixture, and structural division into subpopulations, showing high tolerance to deviations from the assumptions of the model. Computer simulations also show that the proposed method outperforms other leading approaches when the inference concerns recent timeframes. Analysis of data from a variety of human and animal populations gave results in agreement with previous estimations by other methods or with records of historical events.
Abstract
The vertebrate fossil record of the Pampean Region of Argentina occupies an important place in South American vertebrate paleontology. An abundance of localities has long been the main basis ...for constructing the chronostratigraphical/geochronological scale for the late Neogene–Quaternary of South America, as well as for understanding major patterns of vertebrate evolution, including the Great American Biotic Interchange. However, few independently-derived dates are available for constraining this record. In this contribution, we present new
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Ar dates on escorias (likely the product of meteoric impacts) from the Argentinean Atlantic coast and statistically-based biochronological analyses that help to calibrate Late Miocene–Pliocene Pampean faunal successions. For the type areas of the Montehermosan and Chapadmalalan Ages/Stages, our results delimit their age ranges to 4.7–3.7 Ma and ca. 3.74–3.04 Ma, respectively. Additionally, from Buenos Aires Province, dates of 5.17 Ma and 4.33 Ma were recovered for “Huayquerian” and Montehermosan faunas. This information helps to better calibrate important first appearances of allochthonous taxa in South America, including one of the oldest records for procyonids (7.24–5.95 Ma), cricetids (6.95–5.46 Ma), and tayassuids (> 3.74 Ma, oldest high-confidence record). These results also constrain to ca. 3 Ma the last appearances of the autochthonous sparassodonts, as well as terror birds of large/middle body size in South America. South American faunal turnover during the late Neogene, including Late Pliocene extinctions, is interpreted as a consequence of knock-on effects from global climatic changes and initiation of the icehouse climate regime.
The Andean cloud forests of western Colombia and Ecuador are home to several endemic mammals; members of the Oryzomyini, the largest Sigmodontinae tribe, are extensively represented in the region. ...However, our knowledge about this diversity is still incomplete, as evidenced by several new taxa that have been described in recent years. Extensive field work in two protected areas enclosing remnants of Chocó montane forest recovered a high diversity of small mammals. Among them, a medium-sized oryzomyine is here described as a new genus having at least three new species, two of them are named and diagnosed. Although externally similar to members of the genera Nephelomys and Tanyuromys, the new genus has a unique molar pattern within the tribe, being characterized by a noticeable degree of hypsodonty, simplification, lamination, and third molar compression. A phylogeny based on a combination of molecular markers, including nuclear and mitochondrial genes, and morphological data recovered the new genus as sister to Mindomys, and sequentially to Nephelomys. The new genus seems to be another example of a sigmodontine rodent unique to the Chocó biogeographic region. Its type species inhabits cloud forest between 1,600 and 2,300 m in northernmost Ecuador (Carchi Province); a second species is restricted to lower montane forest, 1,200 m, in northern Ecuador (Imbabura Province); a third putative species, here highlighted exclusively by molecular evidence from one immature specimen, is recorded in the montane forest of Reserva Otonga, northern Ecuador (Cotopaxi Province). Finally, the new genus is also recorded in southernmost Colombia (Nariño Department), probably represented there also by a new species. These species are spatially separated by deep river canyons through Andean forests, resulting in marked environmental discontinuities. Unfortunately, Colombian and Ecuadorian Pacific cloud forests are under rapid anthropic transformation. Although the populations of the type species are moderately abundant and occur in protected areas, the other two persist in threatened forest fragments.
Genomic CNVs increase the risk for early-onset neurodevelopmental disorders, but their impact on medical outcomes in later life is still poorly understood. The UK Biobank allows us to study the ...medical consequences of CNVs in middle and old age in half a million well-phenotyped adults.
We analysed all Biobank participants for the presence of 54 CNVs associated with genomic disorders or clinical phenotypes, including their reciprocal deletions or duplications. After array quality control and exclusion of first-degree relatives, we compared 381 452 participants of white British or Irish origin who carried no CNVs with carriers of each of the 54 CNVs (ranging from 5 to 2843 persons). We used logistic regression analysis to estimate the risk of developing 58 common medical phenotypes (3132 comparisons).
Many of the CNVs have profound effects on medical health and mortality, even in people who have largely escaped early neurodevelopmental outcomes. Forty-six CNV-phenotype associations were significant at a false discovery rate threshold of 0.1, all in the direction of increased risk. Known medical consequences of CNVs were confirmed, but most identified associations are novel. Deletions at 16p11.2 and 16p12.1 had the largest numbers of significantly associated phenotypes (seven each). Diabetes, hypertension, obesity and renal failure were affected by the highest numbers of CNVs. Our work should inform clinicians in planning and managing the medical care of CNV carriers.
The Andean cloud forests of Ecuador are home to several endemic mammals. Members of the Thomasomyini rodents are well represented in the Andes, with
being the largest genus (47 species) of the ...subfamily Sigmodontinae. Within this tribe, however, there are genera that have escaped a taxonomic revision, and
Thomas, 1897, constitutes a paradigmatic example of these "forgotten" Andean cricetids. Described more than a century ago, current knowledge of this externally unmistakable montane rodent is very limited, and doubts persist as to whether or not it is monotypic. After several years of field efforts in Ecuador, a considerable quantity of specimens of
were collected from various localities representing both Andean chains. Based on an extensive genetic survey of the obtained material, we can demonstrate that what is currently treated as
in Ecuador is a complex comprising at least five new species which are described in this paper. In addition, based on these noteworthy new evidence, we amend the generic diagnosis in detail, adding several key craniodental traits such as incisor procumbency and microdonty. These results indicate that
probably has a hidden additional diversity in large parts of the Colombian and Peruvian territories, inviting a necessary revision of the entire genus.
Genome-wide association studies (GWAS) have proved to be a powerful approach for gene discovery in schizophrenia; their findings have important implications not just for our understanding of the ...genetic architecture of the disorder, but for the potential applications of personalised medicine through improved classification and targeted interventions. In this article we review the current status of the GWAS literature in schizophrenia including functional annotation methods and polygenic risk scoring, as well as the directions and challenges of future research. We consider recent findings in East Asian populations and the advancements from trans-ancestry analysis, as well as the insights gained from research looking across psychiatric disorders.
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