News, literature, and events in the ethical, social, and legal implications of psychiatric, neurologic, and behavioral genetics. 
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   Vol. 2, No. 1          February 2015

A mistaken version of this issue of the Braingenethics Update accidentally went out minutes ago. Our sincerest apologies -- this is the corrected version. 

This issue of Braingenethics Update features literature, news, and a commentary regarding the genetic and clinical heterogeneity of schizophrenia and autism spectrum disorder.  
Schizophrenia(s) and Autism(s)

Whole-Genome Sequencing of Quartet Families with Autism Spectrum Disorder (ASD)
By Ryan KC Yuen et al. 

Using whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), the authors found that most (69.4%) of the affected siblings carried different ASD-relevant mutations. Siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and nongenic susceptibility variants in research and in clinical diagnostics.

More Differences Than Similarities Are Found in Autistic Siblings
By Benedict Carey

Most siblings with a diagnosis of autism do not share the same genetic risk factors for the disorder and are as distinct in their behaviors as any brothers and sisters, scientists reported in Nature Medicine on a study that came as a surprise to many doctors, if not to parents.

“Autisms” a More Appropriate Term than “Autism,” Geneticists Say
By Will Boggs

The DNA of Autism Spectrum Disorder-affected individuals varies remarkably, says a team of geneticists studying 85 quartet families with ASD. Two-thirds of brothers and sisters with ASD show different genetic changes, which raises the question of whether it is misleading to continue using the singular term, autism, when so many different genetic forms exist. 

Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies
By Javier Arnedo et al. 

In a large genome-wide association study of cases with schizophrenia and controls, the authors concluded that schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes. 

Schizophrenia or Schizophrenias? The Challenge of Genetic Parsing of a Complex Disorder
By Assen Jablensky

Published in tandem with the report by Arnedo et al. in the American Journal of Psychiatry, this editorial analyzes the challenges faced by geneticists supporting the view that schizophrenia is not a nosological monolith but instead a collection of partially overlapping clinical syndromes.

Unpublished Comment on “Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies”
By Gerome Breen et al. 

The authors respond to the study by Arnedo et al. by calling into question the validity of their findings regarding the genetic basis for the subtypes of schizophrenia that they identified.
The Smartest Questions to Ask About Intelligence
By Alison Gopnik

Gopnik suggests that we’re asking the wrong questions when it comes to parsing whether or not intelligence is innate. Thinking in terms of “innate talent” often leads to a kind of fatalism. The most important feature of human beings is our ability to transform our physical and social environments. 



Trans-NIH Workshop to Explore the Ethical, Legal, and Social Implications (ELSI) of Citizen Science
By Genome TV 

Citizen science is an approach to research that involves the public directly in the research process itself as partners and collaborators. The purpose of this workshop is to identify the ELSI challenges raised by citizen science in the context of biomedical research and identify ways for the National Institutes of Health (NIH) to address these ELSI issues. The term "biomedical" is used in the broadest sense to include a wide range of research related to the NIH mission: biological, biomedical, behavioral, social, environmental, and clinical studies that relate to understanding health and disease.

To contribute a news item, an academic article, or an event on the ethical, legal, and social implications of psychiatric, neurological, and behavioral genetics research please email us.

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CEER Commentary

Challenging Monolithic Conceptions of Complex Disorders: Schizophrenia and Autism Spectrum Disorder
By Chelsea A. Jack and Mark B. Herzog

Two studies published this month—one about schizophrenia and the other about autism spectrum disorder—describe genetic and clinical heterogeneity among people with the disorders, suggesting that the diagnoses refer to many entities, not just one.

In the Literature 

What Adolescents Enrolled in Genomic Addiction Research Want to Know about Conflicts of Interest
By Marilyn E. Coors, Kristen M. Raymond, Shannon K. McWilliams, Christian J. Hopfer, and Susan K. Mikulich-Gilbertson

In a study that surveyed 273 adolescents enrolled in genomic addiction research, most participants reported that the disclosure of conflicts of interest would not undermine their trust in researchers. 

The Inclination to Evil and the Punishment of Crime – from the Bible to Behavioral Genetics 
By Azgad Gold and Paul S. Appelbaum

Scientific data pertaining to the behavioral genetics of violent behavior provides a new context for an old dilemma regarding criminal responsibility and punishment: if the inclination to violent behavior is inherent in someone's nature, how should it affect punishment for crime? Should it be considered as a mitigating or an aggravating factor? Given psychiatrists’ increasing involvement in providing testimony on behavioral genetics in the criminal justice system, this paper first provides the necessary background required for understanding how this question arises and reviews the relevant literature. Then, the authors address this question from the perspective of the Bible and its commentators.

Brain-Derived Neurotrophic Factor Epigenetic Modifications Associated with Schizophrenia-like Phenotype Induced by Prenatal Stress in Mice
By Erbo Dong et al. 

Prenatal stress (PRS) is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that PRS induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ, including the gene for brain-derived neurotrophic factor. Based on the results of this study, because patients with psychosis and PRS mice showed a similar epigenetic signature, PRS mice may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with SZ.

Evidence for Autism Spectrum Disorder in Jacobsen Syndrome: Identification of a Candidate Gene in Distal 11q
By Natacha Akshoomoff, Sarah Mattson, and Paul Grossfeld

In this prospective study, 17 patients with 11q terminal deletion disorder – also called Jacobsen syndrome – underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization. The authors found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.

A Genetic Nexus of Obesity and Smoking 
By Eric Sarlin

The hypothesis that obesity and nicotine addiction have common genetic and biological roots is buttressed by a recent NIDA-supported study. Researchers showed that some gene variants that influence body mass index also shape smoking behaviors.

Epigenetic Modification of the Oxytocin Receptor Gene Influences the Perception of Anger and Fear in the Human Brain
By Meghan H. Puglia, Travis S. Lillard, James P. Morris and Jessica J. Connelly

The authors hypothesized that variability in DNA methylation of the oxytocin receptor gene (OXTR) impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, they established a relationship between OXTR methylation and neural activity in response to emotional face processing. Their findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype, including susceptibility or resilience to disease.

By Irving Gottesman and Matt McGue

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease or other phenotypes and distal genomics, have emerged as an important concept in the study of complex neuropsychiatric diseases. They represent simpler clues, in principle, to genetic underpinnings than the disease syndrome itself, thus promoting the prescient view embodied in the recent emphasis on new research domain criteria that psychiatric diagnoses can be optimally deconstructed in ways that allow discovery of their etiology by focusing on endophenotypic dimensions rather than categories. 

Psychological Status in Female Carriers of Premutation FMR1 Allele Showing a Complex Relationship with the Size of CGG Expansion
By Danuta Loesch et al. 

The authors utilized a sample of 299 adult females aged between 19 and 86 years, carrying fragile X mental retardation (FMR1) alleles with small CCG expansions ranging from 50 to 141 repeats to analyze the relationships between psychological symptoms as assessed by the Symptom Checklist-90-Revised (SCL-90-R) and the size of the CGG repeat in the FMR1 gene. There were highly significant (negative) correlations between the size of the CGG repeat and a great majority of SCL-90-R subscale scores and all the global indices, suggesting that carriers of premutations in the mid-size CGG repeat range may be at greatest risk for the development of psychiatric disorder.
Copyright © 2014 Center for Excellence in Ethical, Legal, and Social Implications of Psychiatric, Neurologic, and Behavioral Genetics, All rights reserved.

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