The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p (τc)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29×10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

Teenagers and Precision Psychiatry: A Window of Opportunity

<b><i>Objective:</i></b> Precision medicine raises hope for translating genetic-based knowledge about psychiatric risks into mental health benefits by motivating health-related, risk-reducing behaviors. Teenagers (ages 14–17) are an important age-group to engage in preventive efforts but, their views about psychiatric genetics are understudied. <b><i>Method:</i></b> An online survey with a nationally representative sample of teenagers (<i>n</i> = 417) was conducted. Participants were randomly assigned to receive 1 of 2 handouts, 1 emphasizing the genetic underpinnings of psychiatric conditions; the other agency-oriented and focusing on gene-environment interactions. Survey questions queried their views about behavioral changes in response to psychiatric genetic risk information and expressed willingness to undertake them. Participants’ decision-making characteristics (i.e., self-efficacy, empowerment, intolerance of uncertainty, and sensation-seeking) were assessed at baseline. <b><i>Results:</i></b> Teenagers strongly valued the information provided and its potential usefulness for their mental health. Information about psychiatric genetics alone impacted views about the causes of mental illness. Contrary to our hypothesis, the type of handout did not impact participants’ expressed willingness to make behavioral changes to reduce their risk of developing a psychiatric condition, but their sense of empowerment played a key role in their responses. <b><i>Conclusion:</i></b> Educating teenagers about gene-environment interactions may help facilitate the translational efforts of precision psychiatry. Research with teenagers across racial/ethnic groups, especially those with family histories, is needed to better understand the factors that impact teenagers’ empowerment in psychiatric genomic settings and to identify measures, including the best enablers of empowerment (e.g., educators, parents), which would allow them to reap the benefits of precision psychiatry.

Journey into Genes: Cultural Values and the (Near) Future of Genetic Counselling in Mental Health

Through a case narrative set in the near future, this chapter explores some of the cultural and values issues that are raised by recent advances in genetics and associated personalised medicine. On first inspection, these advances might be thought to resolve or at any rate ameliorate the values issues that arise in the context of shared clinical decision-making as the basis of personalised mental health practice in genetic counselling. On the contrary, however, as the case narrative illustrates, the values issues are considerably amplified. This is an instance of the ‘Science Driven’ principle of values-based practice: that the practical impact of advances in medical science and technology is to widen patients’ choices and with choices go values. The result is that advances in medical science and technology drive the need for enhanced values-based as well as evidence-based practice in responding to the challenges presented by personalised clinical care. The emerging resources for responding to these challenges in the context of psychiatric genetic counselling are described.