Category Archives: Human Genetics

PUBLIC RELEASE DATE:

9-Oct-2014

Contact: Mary Beth O'Leary moleary@cell.com 617-397-2802 Cell Press @CellPressNews

Neurodevelopmental disorders such as Down syndrome and autism-spectrum disorder can have profound, lifelong effects on learning and memory, but relatively little is known about the molecular pathways affected by these diseases. A study published by Cell Press October 9th in the American Journal of Human Genetics shows that neurodevelopmental disorders caused by distinct genetic mutations produce similar molecular effects in cells, suggesting that a one-size-fits-all therapeutic approach could be effective for conditions ranging from seizures to attention-deficit hyperactivity disorder.

"Neurodevelopmental disorders are rare, meaning trying to treat them is not efficient," says senior study author Carl Ernst of McGill University. "Once we fully define the major common pathways involved, targeting these pathways for treatment becomes a viable option that can affect the largest number of people."

A large fraction of neurodevelopmental disorders are associated with variation in specific genes, but the genetic factors responsible for these diseases are very complex. For example, whereas common variants in the same gene have been associated with two or more different disorders, mutations in many different genes can lead to similar diseases. As a result, it has not been clear whether genetic mutations that cause neurodevelopmental disorders affect distinct molecular pathways or converge on similar cellular functions.

To address this question, Ernst and his team used human fetal brain cells to study the molecular effects of reducing the activity of genes that are mutated in two distinct autism-spectrum disorders. Changes in transcription factor 4 (TCF4) cause 18q21 deletion syndrome, which is characterized by intellectual disability and psychiatric problems, and mutations in euchromatic histone methyltransferase 1 (EHMT1) cause similar symptoms in a disease known as 9q34 deletion syndrome.

Interfering with the activity of TCF4 or EHMT1 produced similar molecular effects in the cells. Strikingly, both of these genetic modifications resulted in molecular patterns that resemble those of cells that are differentiating, or converting from immature cells to more specialized cells. "Our study suggests that one fundamental cause of disease is that neural stem cells choose to become full brain cells too early," Ernst says. "This could affect how they incorporate into cellular networks, for example, leading to the clinical symptoms that we see in kids with these diseases."

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The American Journal of Human Genetics, Chen et al.: "Molecular convergence of neurodevelopmental disorders."

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Multiple neurodevelopmental disorders have a common molecular cause

To reduce false positives when identifying genetic variations associated with human disease through genome-wide association studies (GWAS), Dartmouth researchers have identified nine traits that are not dependent on P values to predict single nucleotide polymorphisms (SNP) reproducibility as reported in Human Genetics on October 2, 2014.

Reproducibility rates of SNPs based solely on P values is low. Dartmouth authors' analysis of GWAS studies published in Human Genetics showed a 1-5 percent replication rate.

"It is important to improve our ability to select SNPs for validation using a formalized process. In this paper, we propose a combination of traits that improve replication success," said first author Ivan P. Gorlov, PhD, DSC, associate professor of Community and Family Medicine, Geisel School of Medicine at Dartmouth.

The team assigned a value of zero or one to nine different predictors. To compute the Replication Score (RS), one totals the individual scores for all significant predictors. The predictors include "Online Mendelian Inheritance in Man" (OMIM, a list of genetically caused diseases), receptors, kinases, growth factors, transcription factors, tissue specific, plasma membrane localization, nuclear localization and conversation index. The authors provided detailed information to construct the RS in supplementary material to the paper.

An RS score is not disease specific but shows the potential for impact on human disease. "The disease-associated genes have something in common," said Gorlov. "And we know what specific characteristics should be present to ensure the SNP is likely to be replicated."

Gorlov says the empirical model can be used to select SNPs for validation and prioritization. "We believe that RS-based SNP prioritization may provide guidance for more targeted and powered approach to detecting the disease-associated SNPs with small effect size," he concluded.

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The above story is based on materials provided by The Geisel School of Medicine at Dartmouth. Note: Materials may be edited for content and length.

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Reproducibility score for SNPs associated with human disease in GWAS

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Newswise To reduce false positives when identifying genetic variations associated with human disease through genome-wide association studies (GWAS), Dartmouth researchers have identified nine traits that are not dependent on P values to predict single nucleotide polymorphisms (SNP) reproducibility as reported in Human Genetics on October 2, 2014.

Reproducibility rates of SNPs based solely on P values is low. Dartmouth authors analysis of GWAS studies published in Nature Genetics showed a 1-5 percent replication rate.

It is important to improve our ability to select SNPs for validation using a formalized process. In this paper, we propose a combination of traits that improve replication success, said first author Ivan P. Gorlov, PhD, DSC, associate professor of Community and Family Medicine, Geisel School of Medicine at Dartmouth.

The team assigned a value of zero or one to nine different predictors. To compute the Replication Score (RS), one totals the individual scores for all significant predictors. The predictors include Online Mendelian Inheritance in Man (OMIM, a list of genetically caused diseases), receptors, kinases, growth factors, transcription factors, tissue specific, plasma membrane localization, nuclear localization and conversation index. The authors provided detailed information to construct the RS in supplementary material to the paper.

An RS score is not disease specific but shows the potential for impact on human disease. The disease-associated genes have something in common, said Gorlov. And we know what specific characteristics should be present to ensure the SNP is likely to be replicated

Gorlov says the empirical model can be used to select SNPs for validation and prioritization. We believe that RS-based SNP prioritization may provide guidance for more targeted and powered approach to detecting the disease-associated SNPs with small effect size, he concluded.

This work was supported in part by the National Institutes of Health U19 CA148127 Grant and the National Institutes of Health Grants 5 P30 CA016672, LM009012, LM010098 and GM103534. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

About Norris Cotton Cancer Center at Dartmouth-Hitchcock Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institutes Comprehensive Cancer Center designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.

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Dartmouth Researchers Develop Reproducibility Score for SNPs Associated with Human Disease in GWAS

PUBLIC RELEASE DATE:

8-Oct-2014

Contact: Robin Dutcher robin.Dutcher@hitchcock.org 603-653-9056 The Geisel School of Medicine at Dartmouth

Lebanon, NH, 10/8/14 To reduce false positives when identifying genetic variations associated with human disease through genome-wide association studies (GWAS), Dartmouth researchers have identified nine traits that are not dependent on P values to predict single nucleotide polymorphisms (SNP) reproducibility as reported in Human Genetics on October 2, 2014.

Reproducibility rates of SNPs based solely on P values is low. Dartmouth authors' analysis of GWAS studies published in Nature Genetics showed a 1-5 percent replication rate.

"It is important to improve our ability to select SNPs for validation using a formalized process. In this paper, we propose a combination of traits that improve replication success," said first author Ivan P. Gorlov, PhD, DSC, associate professor of Community and Family Medicine, Geisel School of Medicine at Dartmouth.

The team assigned a value of zero or one to nine different predictors. To compute the Replication Score (RS), one totals the individual scores for all significant predictors. The predictors include "Online Mendelian Inheritance in Man" (OMIM, a list of genetically caused diseases), receptors, kinases, growth factors, transcription factors, tissue specific, plasma membrane localization, nuclear localization and conversation index. The authors provided detailed information to construct the RS in supplementary material to the paper.

An RS score is not disease specific but shows the potential for impact on human disease. "The disease-associated genes have something in common," said Gorlov. "And we know what specific characteristics should be present to ensure the SNP is likely to be replicated"

Gorlov says the empirical model can be used to select SNPs for validation and prioritization. "We believe that RS-based SNP prioritization may provide guidance for more targeted and powered approach to detecting the disease-associated SNPs with small effect size," he concluded.

###

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Researchers develop reproducibility score for SNPs associated with human disease in GWAS

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Newswise The Gordon and Betty Moore Foundation today announced the University of Chicagos Matthew Stephens as the recipient of a Moore Investigator in Data-Driven Discovery award. Stephens, a professor in statistics and human genetics, is among 14 scientists from academic institutions nationwide who will receive a total of $21 million over five years to catalyze new data-driven scientific discoveries. Stephens grant is for $1.5 million.

These Moore Investigator Awards are part of a $60 million, five-year Data-Driven Discovery Initiative within the Gordon and Betty Moores Science Program. The initiativeone of the largest privately funded data scientist programs of its kindis committed to enabling new types of scientific breakthroughs by supporting interdisciplinary, data-driven researchers.

Science is generating data at unprecedented volume, variety and velocity, but many areas of science dont reward the kind of expertise needed to capitalize on this explosion of information, said Chris Mentzel, program director of the Data-Driven Discovery Initiative. We are proud to recognize these outstanding scientists, and we hope these awards will help cultivate a new type of researcher and accelerate the use of interdisciplinary, data-driven science in academia.

Stephens is a data scientist who develops statistical and computational analysis tools for the large datasets being generated in the biological sciences. Over the last 15 years, Stephens and his collaborators have made seminal contributions to several problems in population genetics, including identifying structure (clusters) in genetic data, and modeling correlations among genetic variants.

The methods for identifying structure, which Stephens developed with his collaborators (Jonathan Pritchard, Peter Donnelly and Daniel Falush), have driven scientific discoveries in hundreds of organisms. Science papers in 2002, 2003, and 2004 used their method to elucidate the genetic structure of human populations, the Heliobacter pylori stomach bacterium, and domestic dog breeds, respectively. The original paper of Stephens and his collaborators has been cited more than 11,000 times. And, in an example of the potential for cross-fertilization of ideas across disciplines, similar methods have also become popular in machine learning to identify structure in large collections of text documents.

Stephenss work modeling correlations among genetic variants began with a paper in 2003, with graduate student Na Li, PhD03. At the time scientists were grappling with a problem: they had an elegant model (based on work by UChicagos Richard Hudson, professor in ecology & evolution) relating these correlations to the underlying recombination process, which mixes a parents genetic material before transmission to an offspring, but these models were computationally intractable for even small datasets.

Li and Stephens solved this problem by simplifying the model enough to make it computationally tractable. This new simplified model has found widespread application in the last 10 years: Stephens, Li and their collaborators used their model to demonstrate that most recombination in human genes occurs in relatively narrow channels (``hotspots) rather than being spread uniformly. And thousands of scientists conducting genomic studies now make regular use of these models to impute missing genotype data to substantially improve the efficacy of their studies.

Stephenss recent focus has been on developing methods for data integration combining information on multiple related processes. An important application of these methods which he has been pursuing with collaborators, including Yoav Gilad, Jonathan Pritchard and Anna DiRienzo - is to combine information measured on cellular processes, such as gene expression, and transcription factor binding, to help understand the mechanisms of genetic regulation within living cells.

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Moore Foundation Selects Matthew Stephens for Data-Driven-Discovery Grant

The worlds largest study into the genetics behind human height has discovered the traits vast complexity.

Researchers at The University of Queensland took a leading role in the analysis of more than a quarter of a million samples, finding hundreds of new genes that play a role in determining height.

Co-senior investigator Professor Peter Visscher, from UQs Queensland Brain Institute (QBI), said the discovery would help provide a model for genetic studies of other human traits and of diseases such as psychiatric disorders and dementia.

Just as neuroscientists use experimental organisms as a model to study brain function, geneticists use human height as a model trait to study genetic variation, he said.

The study involved more than 300 organisations across the world and found 697 DNA variants which influence height.

Joint-lead author and QBI researcher Dr Jian Yang said the findings were significant because they proved exactly how complicated human height is.

The DNA variant with the largest effect on height only has an impact of about five millimetres, and most of the other variants have a much smaller effect, Dr Yang said.

Taken together, all DNA variants we discovered account for height differences spanning approximately 11 centimetres.

This shows that the genetic basis for height isnt controlled by a single gene or small group of genes there are thousands of genes involved.

Its estimated that about 80 per cent of a normal healthy individuals height is controlled by heritable genetic factors, and weve only discovered around one-fifth of those genes.

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Genetic building blocks of height revealed

PUBLIC RELEASE DATE:

6-Oct-2014

Contact: Debbie Jacobson djacobson@aap.org 847-434-7084 American Academy of Pediatrics @AmerAcadPeds

SAN DIEGO Award-winning fashion photographer Rick Guidotti crisscrossed the globe taking photos for renowned clients such as Yves Saint Laurent, Revlon and GQ. Now, he uses his eye for beauty to capture images of children and adults with genetic, physical, cognitive and behavioral differences.

Guidotti will share photos he has taken of children with conditions ranging from autism to Fragile X syndrome during a keynote address at the American Academy of Pediatrics (AAP) National Conference & Exhibition. He also will talk about his work to give a voice to the faces in the photos and educate others during his presentation from 11:30-noon on Saturday, Oct. 11 in Ballroom 20 of the San Diego Convention Center.

CEO of a nonprofit group called Positive Exposure, Guidotti is on a mission to change public perceptions of those with differences so they are seen as people first rather than as a disease or victim.

He made the leap from fashion photographer to founder of Positive Exposure in 1998 after a chance encounter with a girl who had albinism. He was mesmerized by her white hair and pale skin. Yet when he did some research on the condition, he was disturbed by the images in medical textbooks of children standing up against a wall with a black bar across their eyes.

He left the fashion industry and created Positive Exposure to show the beauty in human diversity and human genetics and promote a more inclusive, compassionate world where differences are celebrated. Initial images were published in the June 1998 issue of LIFE magazine as a cover story titled "Redefining Beauty."

"We need to start talking about diversity constantly," Guidotti said. "That's the only way we're going to break down those fears and stigma and address discrimination and prejudice in the workforce, in the community, in our churches, in our synagogues, wherever we happen to be."

Guidotti's photographic exhibition, called Positive Exposure: The Spirit of Difference, premiered at the People's Genome Celebration in June 2001. It also has been in the Smithsonian's National Museum of Natural History in Washington, D.C., and galleries around the world.

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Former fashion photographer celebrates beauty in human diversity

Oct. 5 (UPI) -- Scientists believe they now have a better understanding of what determines height in humans. An international group of researchers came together and studied a group of over 250,000 people from different regions of the world. They located over 400 genome regions that appear to be related to determining height, and they found almost 700 genetic variants.

The research, published in Nature Genetics, claims that around 80 percent of human height is based on genes, while the remaining 20 percent is based on external factors like diet. The researchers involved believe these findings could help treat diseases that can be related to height, like osteoporosis. The study further supports the concept that height is largely based on genetics, as is seen by tall parents bearing taller children. The found genes might help scientists study rare syndromes that cause children to grow unusually tall or unusually little.

2014 United Press International, Inc. All Rights Reserved. Any reproduction, republication, redistribution and/or modification of any UPI content is expressly prohibited without UPI's prior written consent.

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Scientists are closer to understanding human height, new study reports

Human genetics of malaria has uncovered some new clues about susceptibility to severe malaria
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PUBLIC RELEASE DATE:

3-Oct-2014

Contact: Noah Brown nbrown9@partners.org 617-643-3907 Massachusetts General Hospital @MassGeneralNews

It has become common for people who have pets to refer to themselves as "pet parents," but how closely does the relationship between people and their non-human companions mirror the parent-child relationship? A small study from a group of Massachusetts General Hospital (MGH) researchers makes a contribution to answering this complex question by investigating differences in how important brain structures are activated when women view images of their children and of their own dogs. Their report is being published in the open-access journal PLOS ONE.

"Pets hold a special place in many people's hearts and lives, and there is compelling evidence from clinical and laboratory studies that interacting with pets can be beneficial to the physical, social and emotional wellbeing of humans," says Lori Palley, DVM, of the MGH Center for Comparative Medicine, co-lead author of the report. "Several previous studies have found that levels of neurohormones like oxytocin which is involved in pair-bonding and maternal attachment rise after interaction with pets, and new brain imaging technologies are helping us begin to understand the neurobiological basis of the relationship, which is exciting."

In order to compare patterns of brain activation involved with the human-pet bond with those elicited by the maternal-child bond, the study enrolled a group of women with at least one child aged 2 to 10 years old and one pet dog that had been in the household for two years or longer. Participation consisted of two sessions, the first being a home visit during which participants completed several questionnaires, including ones regarding their relationships with both their child and pet dog. The participants' dog and child were also photographed in each participants' home.

The second session took place at the Athinoula A. Martinos Center for Biomedical Imaging at MGH, where functional magnetic resonance imaging (fMRI) which indicates levels of activation in specific brain structures by detecting changes in blood flow and oxygen levels was performed as participants lay in a scanner and viewed a series of photographs. The photos included images of each participant's own child and own dog alternating with those of an unfamiliar child and dog belonging to another study participant. After the scanning session, each participant completed additional assessments, including an image recognition test to confirm she had paid close attention to photos presented during scanning, and rated several images from each category shown during the session on factors relating to pleasantness and excitement.

Of 16 women originally enrolled, complete information and MR data was available for 14 participants. The imaging studies revealed both similarities and differences in the way important brain regions reacted to images of a woman's own child and own dog. Areas previously reported as important for functions such as emotion, reward, affiliation, visual processing and social interaction all showed increased activity when participants viewed either their own child or their own dog. A region known to be important to bond formation the substantia nigra/ventral tegmental area (SNi/VTA) was activated only in response to images of a participant's own child. The fusiform gyrus, which is involved in facial recognition and other visual processing functions, actually showed greater response to own-dog images than own-child images.

"Although this is a small study that may not apply to other individuals, the results suggest there is a common brain network important for pair-bond formation and maintenance that is activated when mothers viewed images of either their child or their dog," says Luke Stoeckel, PhD, MGH Department of Psychiatry, co-lead author of the PLOS ONE report. "We also observed differences in activation of some regions that may reflect variance in the evolutionary course and function of these relationships. For example, like the SNi/VTA, the nucleus accumbens has been reported to have an important role in pair-bonding in both human and animal studies. But that region showed greater deactivation when mothers viewed their own-dog images instead of greater activation in response to own-child images, as one might expect. We think the greater response of the fusiform gyrus to images of participants' dogs may reflect the increased reliance on visual than verbal cues in human-animal communications."

Co-author Randy Gollub, MD, PhD, of MGH Psychiatry adds, "Since fMRI is an indirect measure of neural activity and can only correlate brain activity with an individual's experience, it will be interesting to see if future studies can directly test whether these patterns of brain activity are explained by the specific cognitive and emotional functions involved in human-animal relationships. Further, the similarities and differences in brain activity revealed by functional neuroimaging may help to generate hypotheses that eventually provide an explanation for the complexities underlying human-animal relationships."

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Massachusetts General study suggests neurobiological basis of human-pet relationship