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Developmental Biology - Cerebral Cortex

The Genetic Architecture of Our Brain

The first genetic map of our cerebral cortex identifies more than 300 gene variations influencing its structure and psychology...


The human cerebral cortex is important in human cognition. Katrina L. Grasby et al. combined genetic data with brain magnetic resonance imaging from more than 50,000 people in order to generate a genome-wide analysis of human genetic variation and how it influences cortical surface area and thickness.

From this analysis, they have now identified variations associated with cortical structure that affect cell signaling and gene expression. They also observed overlap between genetic loci affecting cortical structure, brain development, and neuropsychiatric disease.
Our cerebral cortex is the relatively thin and folded, outer "gray matter" layer of our brain — crucial for thinking, information processing, memory, and attention.

Not much has been known about the genetic underpinnings influencing the size and thickness of our cortical surface area. Both have previously been linked to numerous psychiatric traits including schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder (ADHD) and autism. Now, for the first time, 360 scientists from 184 different institutions have contributed in a global effort to identify more than 200 regions of the genome with more than 300 gene variations specifically affecting the cerebral cortex. Regions likely influencing psychiatric and neurologic conditions.

Published in Science, the study was led by co-senior authors Jason Stein PhD, assistant professor, Department of Genetics at the UNC School of Medicine; Sarah Medland PhD, senior research fellow, the QIMR Berghofer Medical Research Institute, Australia; and Paul Thompson PhD, associate director, the Mark and Mary Stevens Neuroimaging and Informatics Institute at the University of Southern California.

Ten years ago, these scientists co-founded the ENIGMA Consortium, an international research network of hundreds of genomic imaging researchers. Their intent is to understand how brain structure and function aligns with diseases, based on brain imaging and genetic data.
Researchers have studied more than 50,000 people using MRI scans and DNA to identify 306 genetic variants which influence brain structure. Genetic variations are simply the slight gene differences that make us unique.

Generally, gene variations contribute to differences in hair color or blood type, while some are involved in diseases. Most of the millions of genetic variants, though, have no known significance. This is why pinpointing genetic variations associated with the size and structure of the cortex is a big deal. Stein and colleagues consider their new genetic roadmap of the brain a sort of "Rosetta stone" that will help translate how some genes impact physical brain structure and neurological consequences for individuals.

Among the findings:

• Some genetic variants are associated with cortical folding, or surface area, while other genetic variants are associated with thickness of the cortex.

• Genes that determine surface area are related to very early development in the fetal cortex.

• Cortical thickness appears to be driven by genes active in the adult cortex.

• People at genetic risk for depression or insomnia are genetically inclined toward having lower surface area.

• People with a genetic risk for Parkinson's disease tend to have higher surface area.

The vast scale of the project allowed for discovery of specific genes that drive brain development and aging in people worldwide. "Most of our previous understanding of genes affecting the brain are from model systems, like mice," adds Stein. "With mice, we can find genes, knock out genes, or over express genes to see how they influence the structure or function of the brain. But there are a couple of problems with this."

One problem is, quite simply, a mouse is not a human. There are many human-specific features that scientists can only study in the human brain.

"The genetic basis for a mouse is very different than the genetic basis for humans," Stein explains, "especially in in the noncoding regions of the genome."

Genes contain DNA, basic human code that translated into action will create proteins which "do" things — such as help your finger muscles type, your heart to beat, or your liver to process toxins.
Only about 3% of the human genome codes for proteins. The vast majority of our genome is noncoding. Much of this noncoding genome isn't shared between mice and humans. It consists of tiny molecular switches that modify gene functions by affecting the amounts of protein being expressed.

Most genetic variants associated with psychiatric disorders are found in the noncoding region of the genome.

These findings can now become a resource for scientists in answering questions about genetic influences on the brain and their relationship to numerous psychiatric conditions.

Abstract
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.

Authors
Katrina L. Grasby, Neda Jahanshad, Jodie N. Painter, Lucía Colodro-Conde, Janita Bralten, Derrek P. Hibar, Penelope A. Lind, Fabrizio Pizzagalli, Christopher R. K. Ching, Mary Agnes B. McMahon, Natalia Shatokhina, Leo C. P. Zsembik, Sophia I. Thomopoulos, Alyssa H. Zhu, Lachlan T. Strike...Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group.


Acknowledgements
The authors thank the California Department of Developmental Services (CDDS) for providing the data used in this study. We are grateful to Sallie Bernard and Irva Hertz-Picciotto for their helpful comments. We also thank two anonymous reviewers, whose comments much improved the manuscript. Finally, we thank Susanne Meza-Keuthen for her support of this study.

Funding None of the authors received specific funding for this work.

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Apr 14 2020   Fetal Timeline   Maternal Timeline   News <


Measurement of brain cortical surface area and thickness from MRI.
CREDIT: K. Courtney; M. R. Glass.


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