Current Psychiatry Reviews - Volume 10, Issue 2, 2014

With the decrease in sequencing cost and the rise of companies providing sequencing services, it is likely that personalized whole-genome sequencing will eventually become an instrument of common medical practice. We write this series of three reviews to help non-geneticist clinicians get ready for the major breakthroughs that are likely to occur in the coming years in the fast-moving field of personalized medicine. This first paper focuses on the fundamental concepts of molecular genetics. We review how recombination occurs during meiosis, how de novo genetic variations including single nucleotide polymorphisms (SNPs), insertions and deletions are generated and how they are inherited from one generation to the next. We detail how genetic variants can impact protein expression and function, and summarize the main characteristics of the human genome. We also explain how the achievements of the Human Genome Project, the HapMap Project, and more recently, the 1000 Genomes Project, have boosted the identification of genetic variants contributing to common diseases in human populations. The second and third papers will focus on genetic epidemiology and clinical applications in personalized medicine.

With the decrease in sequencing costs, personalized genome sequencing will eventually become common in medical practice. We therefore write this series of three reviews to help non-geneticist clinicians to jump into the fastmoving field of personalized medicine. In the first article of this series, we reviewed the fundamental concepts in molecular genetics. In this second article, we cover the key concepts and methods in genetic epidemiology including the classification of genetic disorders, study designs and their implementation, genetic marker selection, genotyping and sequencing technologies, gene identification strategies, data analyses and data interpretation. This review will help the reader critically appraise a genetic association study. In the next article, we will discuss the clinical applications of genetic epidemiology in the personalized medicine area.

The rapid decline of sequencing costs brings hope that personal genome sequencing will become a common feature of medical practice. This series of three reviews aim to help non-geneticist clinicians to jump into the fast-moving field of personalized genetic medicine. In the first two articles, we covered the fundamental concepts of molecular genetics and the methodologies used in genetic epidemiology. In this third article, we discuss the evolution of personalized medicine and illustrate the most recent success in the fields of Mendelian and complex human diseases. We also address the challenges that currently limit the use of personalized medicine to its full potential.

Research into the genetic basis of schizophrenia is advancing rapidly. This review gives a broad overview of results from successive phases of studies in this field, linking these with recent findings and likely future research directions. Among recent findings, large-scale epidemiological studies based on Scandinavian population registers, have provided further evidence of substantial heritability and evidence that a wide range of psychotic and non-psychotic disorders partly share genetic risk factors with schizophrenia. In molecular genetics, large collaborative genomewide association studies (GWAS) are providing evidence of common risk variants, each of small effect, and many more variants are likely to be found as samples sizes increase further. A range of rarer chromosomal copy number variants (CNVs) have been associated with schizophrenia, and both GWAS and CNV studies have provided molecular evidence of genetic overlap between schizophrenia and other disorders. There is increasing interest in phenotypes beyond diagnosis, including further clinical variables and endophenotypes. Next-generation sequencing studies are beginning, with the potential for fast, inexpensive sequencing of the whole genome in large samples, and there is an increasing focus on the functional effects of the candidate risk variants that are being identified.

ADHD and Autism have been considered as two separate disorders and the classification systems make them mutually exclusive. However, there is a long-standing literature on overlapping phenotypes, and a more recent genetic literature on rare variants that have been found in both. This review summarises the clinical, familial and recent genetic overlap and discusses what this might mean for future diagnosis and treatment.

This narrative review aims to provide an overview of the impact of opioid dependence and the contribution of genetics to opioid dependence. Epidemiological data demonstrate that opioid dependence is a global trend with farreaching effects on the social, economic, and health care systems. A review of classical genetic studies of opioid use suggests significant heritability of drug use behavior, however the evidence from molecular genetic studies is inconclusive. Nonetheless, certain genetic variants are important to consider given their role in the pathophysiology of addictive behavior. We undertook a literature review to identify the current state of knowledge regarding the role of genes in opioid dependence. Determining the association of genetic markers could change the current understanding of the various factors contributing to opioid dependence and therefore may improve recognition of individuals at risk for the disorder and prevention and treatment strategies.

Prader-Willi syndrome (PWS) is an imprinting neurodevelopmental disorder resulting from loss of function of paternal PWS critical genomic region on chromosome 15q11-q13. The clinical course in PWS is characterized by neonatal hypotonia with feeding difficulties and failure to thrive. This is followed by onset of hyperphagia leading to obesity. Patients with PWS have several neurobehavioral and psychiatric features including learning disability, autism spectrum disorder, temper tantrums, repetitive behaviors, skin picking, affective disorders and psychosis. In this review, we focus on genotype–phenotype correlations in PWS. We also describe the current protocol for genetic testing to establish the diagnosis, the differential diagnosis of PWS, and the neurobehavioral and psychiatric manifestations and their management.

There is considerable variation in the individualized response to psychotropic drug therapies, which include antidepressants, antipsychotics and mood stabilizers. It has been proposed that the wide interindividual variability in psychotropic drug-response may be attributable to genetic variants. Thus pharmacogenetics may help to accurately predict response to psychotropic treatment, and may be used as guidelines in selecting an appropriate psychotropic treatment in order to maximize drug efficacy and minimize drug toxicity. Although the clinical utility of psychiatric pharmacogenetics is very promising, its adoption in clinical practice has been slow. This resistance may stem from sometimes conflicting findings among pharmacogenetic studies. The failure to replicate these findings may result from a lack of high-quality studies and unresolved methodological issues. In this review we will address methodological and statistical challenges in pharmacogenetic studies and summarize the current pharmacogenetic literature on psychotropic drug-response.

Background: To date, research in the field of genetics in psychiatric illness has yielded inconclusive results. The focus has primarily been on the nuclear genome, with relatively little attention paid to the mitochondrial genome. A growing body of evidence supports the hypothesis that mitochondrial dysfunction may be important in the biology of psychiatric disorders; therefore, we reviewed the literature on mitochondrial abnormalities and adult psychiatric disorders. Methods: We searched EMBASE, PsycINFO and MEDLINE (from inception – September 2011) and identified additional studies through review of reference lists of key articles. Results: Patients with mitochondrial disorders display prominent psychiatric symptomatology, as seen by evidence from cross-sectional studies, case reports and case series. Mitochondrial DNA polymorphisms have been associated with several psychiatric illnesses including bipolar disorder, major depression, and schizophrenia, however, the literature demonstrates conflicting results and most studies have been underpowered. Despite some initial promising findings, the majority of studies have failed to find an association between mitochondrial DNA mutations and psychiatric illness. At the present time, there is not sufficient evidence to implicate any particular mitochondrial genetic variant in any disorder. Mitochondrial epigenetics, mitochondria-glucocorticoid interactions, disruption of neuronal oscillations and medication effects may all represent mechanisms by which mitochondria contribute to psychiatric illness. Conclusions: Patients with mitochondrial disorders can display prominent psychiatric symptoms and patients with psychiatric disorders may have an undiagnosed mitochondrial disorder. Additional studies incorporating larger samples are necessary to determine how mitochondrial genetics are involved in psychiatric illness to confirm these findings. Accumulating evidence also suggests involvement of mitochondrial dysfunction in the pathophysiology of psychiatric disorders, and therapeutic agents that target the mitochondria may be potentially effective treatments for psychiatric illness and merit further investigation.