Do Participants in Genome Sequencing Studies of Psychiatric Disorders Wish to Be Informed of Their Results? A Survey Study

<div><p>Objective</p><p>As large-scale genome sequencing technology advances, concerns surrounding the reporting of individual findings to study volunteers have grown and fueled controversy. This is especially true in mental health research, where the clinical importance of sequencing results is particularly unclear. The ethical, legal, and social issues are being widely debated, but less is known about the attitudes of actual study volunteers toward sequencing studies or what they wish to learn about their DNA sequence and its health implications. This study provides information on psychiatric research volunteers’ attitudes, beliefs, and concerns with respect to participation in DNA sequencing studies and reporting of individual results.</p><p>Method</p><p>We conducted a pilot study using a questionnaire that we developed to assess what information volunteers in an ongoing family study of bipolar disorder would like to receive if they underwent genome sequencing, what they would do with that information, and what concerns they may have.</p><p>Results</p><p>Almost all of the respondents were willing to participate in genome sequencing. Most respondents wished to be informed about all their health-related genetic risks, including risks for diseases without known prevention or treatment. However, few respondents felt well informed about the nature of genome sequencing or its implications for their health, insurability, or offspring.</p><p>Conclusions</p><p>Despite generally positive attitudes toward genome sequencing among study volunteers, most are not fully aware of the special issues raised by genome sequencing. The attitudes of study volunteers should be considered in the debate about the reporting of individual findings from genome sequencing.</p></div

Participant characteristics.

1<p>Denominator is 58 within each category.</p>2<p>Rounded to nearest whole percent.</p

What would be the most important things to know?

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101111#pone-0101111-g001" target="_blank">Figure 1</a> illustrates participants’ responses to the survey question, “What would be the most important [health information] to know?” in a word cloud, with size directly related to the commonality of the word used in the responses. The word cloud was created using online software at <a href="http://www.tagxedo.com" target="_blank">www.tagxedo.com</a>. We entered the text from the participants’ responses free responses. For clarity, we removed common everyday words, combined related words, and set the emphasis to 80%, the maximum word count to 50, tightness to 100%, color variation to 50%, and spread frequency to 20. We edited the style and format for legibility.</p

Highlighted survey responses.

1<p>Denominator may not equal 58 due to missing responses or multiple answers possible.</p>2<p>Rounded to nearest whole percent.</p

Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study

Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10; rs78015114, p=1·31×10; rs74795342, p=3·31×10; and rs75222709, p=3·50×10). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program

The International Consortium on Lithium Genetics (ConLiGen): An Initiative by the NIMH and IGSLI to Study the Genetic Basis of Response to Lithium Treatment

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic ‘fashions’, and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health, lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts

PLPHP deficiency:clinical, genetic, biochemical, and mechanistic insights

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of &gt;9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P =  5.87 × 10 -  9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P =  4.53 × 10 -  9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS