scholarly journals Decreases in Brain Size and Encephalization in Anatomically Modern Humans

2021 ◽  
pp. 1-14
Author(s):  
Jeff Morgan Stibel
Keyword(s):  
Human Brain ◽  
Brain Size ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Modern Humans ◽  
Brain Mass ◽  
Evolutionary Consequence ◽  
The Past ◽  
Anatomically Modern Humans ◽  
Cognitive Faculties

Growth in human brain size and encephalization is well documented throughout much of prehistory and believed to be responsible for increasing cognitive faculties. Over the past 50,000 years, however, both body size and brain mass have decreased but little is known about the scaling relationship between the two. Here, changes to the human brain are examined using matched body remains to determine encephalization levels across an evolutionary timespan. The results find decreases to encephalization levels in modern humans as compared to earlier Holocene <i>H. sapiens</i> and Late Pleistocene anatomically modern <i>Homo</i>. When controlled for lean body mass, encephalization changes are isometric, suggesting that much of the declines in encephalization are driven by recent increases in obesity. A meta-review of genome-wide association studies finds some evidence for selective pressures acting on human cognitive ability, which may be an evolutionary consequence of the more than 5% loss in brain mass over the past 50,000 years.

scholarly journals Genetic epidemiology and Mendelian randomization for informing disease therapeutics: conceptual and methodological challenges

2017 ◽  
Author(s):  
Lavinia Paternoster ◽  
Kate Tilling ◽  
George Davey Smith
Keyword(s):  
Genetic Epidemiology ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Disease Treatment ◽  
The Past ◽  
Genome Wide ◽  
Perceived Benefit ◽  
Progression Of Disease ◽  
High Yields

The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets (1-4), but this has yet to be realised at a level reflecting expectation. One reason for this, we suggest, is that GWAS to date have generally not focused on phenotypes that directly relate to the progression of disease, and thus speak to disease treatment.

Genetic Methodologies and Applications

2017 ◽  
Author(s):  
Shaun M. Purcell
Keyword(s):  
Mental Illness ◽  
Genetic Risk ◽  
Genetic Basis ◽  
Common Mental Disorders ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
The Past ◽  
Genome Wide ◽  
Experimental Approaches ◽  
Large Families

Mental illness is highly heritable, yet it has been difficult historically to identify the specific genes that comprise that risk. This difficulty resides in the fact that the genetic risk for all common mental disorders is polygenic, with perhaps hundreds of genetic variations, each of small effect, contributing to the overall risk. Despite these challenges, the field has made dramatic advances over the past decade in beginning to understand the genetic basis of mental illness. This chapter provides an overview of the experimental approaches used, beginning with epidemiology and population genetics to define the heritability of an illness, to classic studies of large families and linkage disequilibrium analysis, to genome-wide investigations including genome-wide association studies (GWAS), exome sequencing, and whole genome sequencing. Increasingly, these genetic advances are being understood within the biological context of disease pathophysiology.

scholarly journals Multivariate genome-wide association studies on the tissue compartments of human brain identify novel loci underpinning brain development and neuropsychiatric outcomes.

2021 ◽  
Author(s):  
Chun Chieh Fan ◽  
Robert Loughnan ◽  
Diliana Pechva ◽  
Chi-Hua Chen ◽  
Donald Hagler ◽  
...  
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Risk Tolerance ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Imaging Features ◽  
Genome Wide ◽  
Neuropsychiatric Diseases ◽  
Tissue Compartments

It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 unique genetic loci that explained more than 50% of the average heritability across imaging features sensitive to tissue compartments. The genome-wide signals are strongly overlapped with neuropsychiatric diseases, cognitive functions, risk tolerance, and immune responses. Our results implicate the shared molecular mechanisms between tissue microstructures of brain and neuropsychiatric outcomes with astrocyte involvement in the early developmental stage.

scholarly journals Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer’s Disease Brain Tissue Reveals Disease-Associated Signatures

2021 ◽  
Vol 12 ◽  
Author(s):  
Whitaker Cohn ◽  
Mikhail Melnik ◽  
Calvin Huang ◽  
Bruce Teter ◽  
Sujyoti Chandra ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Brain Tissue ◽  
Extracellular Vesicles ◽  
Clinical Symptoms ◽  
Association Studies ◽  
Acyl Chain ◽  
Integrated Analysis ◽  
Genome Wide Association Studies

Alzheimer’s disease (AD) is the most common cause of dementia, yet there is no cure or diagnostics available prior to the onset of clinical symptoms. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that are released from almost all types of cell. Genome-wide association studies have linked multiple AD genetic risk factors to microglia-specific pathways. It is plausible that microglia-derived EVs may play a role in the progression of AD by contributing to the dissemination of insoluble pathogenic proteins, such as tau and Aβ. Despite the potential utility of EVs as a diagnostic tool, our knowledge of human brain EV subpopulations is limited. Here we present a method for isolating microglial CD11b-positive small EVs from cryopreserved human brain tissue, as well as an integrated multiomics analysis of microglial EVs enriched from the parietal cortex of four late-stage AD (Braak V-VI) and three age-matched normal/low pathology (NL) cases. This integrated analysis revealed 1,000 proteins, 594 lipids, and 105 miRNAs using shotgun proteomics, targeted lipidomics, and NanoString nCounter technology, respectively. The results showed a significant reduction in the abundance of homeostatic microglia markers P2RY12 and TMEM119, and increased levels of disease-associated microglia markers FTH1 and TREM2, in CD11b-positive EVs from AD brain compared to NL cases. Tau abundance was significantly higher in AD brain-derived microglial EVs. These changes were accompanied by the upregulation of synaptic and neuron-specific proteins in the AD group. Levels of free cholesterol were elevated in microglial EVs from the AD brain. Lipidomic analysis also revealed a proinflammatory lipid profile, endolysosomal dysfunction, and a significant AD-associated decrease in levels of docosahexaenoic acid (DHA)-containing polyunsaturated lipids, suggesting a potential defect in acyl-chain remodeling. Additionally, four miRNAs associated with immune and cellular senescence signaling pathways were significantly upregulated in the AD group. Our data suggest that loss of the homeostatic microglia signature in late AD stages may be accompanied by endolysosomal impairment and the release of undigested neuronal and myelin debris, including tau, through extracellular vesicles. We suggest that the analysis of microglia-derived EVs has merit for identifying novel EV-associated biomarkers and providing a framework for future larger-scale multiomics studies on patient-derived cell-type-specific EVs.

Pharmacogenetics studies in stroke patients treated with rtPA: a review of the most interesting findings

2021 ◽  
Author(s):  
Laia Llucià-Carol ◽  
Elena Muiño ◽  
Cristina Gallego-Fabrega ◽  
Jara Cárcel-Márquez ◽  
Jesus Martín-Campos ◽  
...  
Keyword(s):  
Association Studies ◽  
Recombinant Tissue Plasminogen Activator ◽  
Genome Wide Association Studies ◽  
Factors Associated ◽  
The Past ◽  
Genome Wide ◽  
Candidate Strategy ◽  
Tissue Plasminogen ◽  
Functional Deterioration

Recombinant tissue-plasminogen activator (rtPA) is the only drug used during the acute phase of stroke. Despite its important benefits, a percentage of patients suffer symptomatic hemorrhagic transformations or a lack of early recanalization rates. These undesirable effects are associated with acute neurological and long-term functional deterioration. For the past 20 years, pharmacogenetic studies have tried to find the genetic risk factors associated with rtPA response. Most of these studies have used a gene-candidate strategy; however, recent genome-wide association studies have emerged indicating that genetic predisposition could modulate rtPA response. This review summarizes the most interesting findings in this field, including which genes and genetic variations are associated with hemorrhagic transformations and recanalization rates after thrombolytic therapy.

scholarly journals Dissecting the phenotype in genome-wide association studies of psychiatric illness

2009 ◽  
Vol 195 (2) ◽  
pp. 97-99 ◽  
Keyword(s):  
Psychiatric Disorders ◽  
Psychiatric Illness ◽  
Genetic Architecture ◽  
Association Studies ◽  
Human Diseases ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
The Past ◽  
Genome Wide

SummaryOver the past 2 years genome-wide association studies have made major contributions to understanding the genetic architecture of many common human diseases. This editorial outlines the development of such studies in psychiatry and highlights the opportunities for advancing understanding of the biological underpinnings and nosological structure of psychiatric disorders.

scholarly journals Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

2020 ◽  
Author(s):  
Evonne McArthur ◽  
David Rinker ◽  
John A. Capra
Keyword(s):  
Complex Traits ◽  
Molecular Level ◽  
Association Studies ◽  
Modern Human ◽  
Modern Humans ◽  
Lung Capacity ◽  
Genome Wide ◽  
Anatomically Modern Humans ◽  
Estimate Heritability ◽  
Genomic Regions

ABSTRACTBackgroundNearly all Eurasians have ∼2% Neanderthal ancestry due to several events of inbreeding between anatomically modern humans and archaic hominins. Previous studies characterizing the legacy of Neanderthal ancestry in modern Eurasians have identified examples of both adaptive and deleterious effects of admixture. However, we lack a comprehensive understanding of the genome-wide influence of Neanderthal introgression on modern human diseases and traits.ResultsWe integrate recent maps of Neanderthal ancestry with well-powered association studies for more than 400 diverse traits to estimate heritability enrichment patterns in regions of the human genome tolerant of Neanderthal ancestry and in introgressed Neanderthal variants themselves. First, we find that variants in regions tolerant of Neanderthal ancestry are depleted of heritability for all traits considered, except skin and hair-related traits. Second, the introgressed variants remaining in modern Europeans are depleted of heritability for most traits; however, we discover that they are enriched for heritability of several traits with potential relevance to human adaptation to non-African environments, including hair and skin traits, autoimmunity, chronotype, bone density, lung capacity, and menopause age. To better understand the phenotypic consequences of these enrichments, we adapt recent methods to test for consistent directional effects of introgressed alleles, and we find directionality for several traits. Finally, we use a direction-of-effect-aware approach to highlight novel candidate introgressed variants that influence risk for disease.ConclusionOur results demonstrate that genomic regions retaining Neanderthal ancestry are not only less functional at the molecular-level, but are also depleted for variation influencing a diverse array of complex traits in modern humans. In spite of this depletion, we identify traits where introgression has an outsized effect. Integrating our results, we propose a framework for using quantification of trait heritability and direction of effect in introgressed regions to understand how Neanderthals were different from modern humans, how selection acted on different traits, and how introgression may have facilitated adaptation to non-African environments.

scholarly journals Dissecting the genetics of complex traits using summary association statistics

2016 ◽  
Author(s):  
Bogdan Pasaniuc ◽  
Alkes L. Price
Keyword(s):  
Complex Traits ◽  
Genetic Basis ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Privacy Concerns ◽  
Individual Level ◽  
The Past ◽  
Genome Wide ◽  
Association Data ◽  
Limit Access

AbstractDuring the past decade, genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with complex traits and diseases. These studies have produced vast repositories of genetic variation and trait measurements across millions of individuals, providing tremendous opportunities for further analyses. However, privacy concerns and other logistical considerations often limit access to individual-level genetic data, motivating the development of methods that analyze summary association statistics. Here we review recent progress on statistical methods that leverage summary association data to gain insights into the genetic basis of complex traits and diseases.

Genetics of Intracranial Aneurysms

Stroke ◽  
2021 ◽  
Author(s):  
Mark K. Bakker ◽  
Ynte M. Ruigrok
Keyword(s):  
Genetic Risk ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Association Studies ◽  
Current Status ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
The Past ◽  
Genome Wide ◽  
Family Based ◽  
Severe Type

Rupture of an intracranial aneurysm leads to aneurysmal subarachnoid hemorrhage, a severe type of stroke which is, in part, driven by genetic variation. In the past 10 years, genetic studies of IA have boosted the number of known genetic risk factors and improved our understanding of the disease. In this review, we provide an overview of the current status of the field and highlight the latest findings of family based, sequencing, and genome-wide association studies. We further describe opportunities of genetic analyses for understanding, prevention, and treatment of the disease.

Genome-wide association studies

2019 ◽  
pp. 51-62
Author(s):  
Thomas W Mühleisen ◽  
Sven Cichon
Keyword(s):  
Basic Concept ◽  
Association Studies ◽  
A Priori ◽  
Genome Wide Association ◽  
Psychiatric Research ◽  
A Priori Knowledge ◽  
Genome Wide Association Studies ◽  
The Past ◽  
Genome Wide ◽  
Technological Developments

Genome-wide association studies (GWAS) have evolved over the past ten years into a very successful tool for investigating the genetic architecture of multifactorial human traits and disorders. One major advantage of GWAS is that they do not require any a priori knowledge about the biological mechanisms underlying the traits and disorders under study. This chapter describes the scientific and technological developments that made GWAS possible and the underlying basic concept of these studies. The chapter considers what has been learned from GWAS in psychiatric research so far, what are the limitations, and looks forward to the future of GWAS.

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