Research Review: Polygenic methods and their application to psychiatric traits

Wray, Naomi R.; Lee, Sang; Mehta, Divya; Vinkhuyzen, Anna A. E.; Dudbridge, Frank; Middeldorp, Christel M.

doi:10.1111/jcpp.12295

Cited by 620 publications

(639 citation statements)

References 129 publications

(134 reference statements)

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“…The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised. Here, we systematically characterized six rare genetic variants of DAT (I312F, T356M, D421N, A559V, E602G, and R615C) identified in patients with neuropsychiatric disorders. We evaluated dopamine uptake and ligand interactions, along with ion coordination and electrophysiological properties, to elucidate functional phenotypes, and applied Zn 2+ exposure and a substituted cysteineaccessibility approach to identify shared structural changes. Three variants (I312F, T356M, and D421N) exhibited impaired dopamine uptake associated with changes in ligand binding, ion coordination, and distinct conformational disturbances. Remarkably, we found that all three variants displayed gain-offunction electrophysiological phenotypes. I312F mediated an increased uncoupled anion conductance previously suggested to modulate neuronal excitability. T356M and D421N both mediated a cocaine-sensitive leakage of cations, which for T356M, was potentiated by Zn 2+ , concurrent with partial functional rescue. Collectively, our findings support that gain of disruptive functions due to missense mutations in SLC6A3 may be key to understanding how dopaminergic dyshomeostasis arises in heterozygous carriers.A substantial proportion of the disease etiology of common psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder, and schizophrenia is attributed genetic components (1). The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18). Despite progress, much of the genetic component remains unaccounted for, and we also have the challenge ahead of translating most of the comprehensive genetic information into an understanding of underlying biological processes, and subsequently into clinically applicable knowledge. Rare variants may provide a unique handle for obtaining new disease insights as they are expected to h...

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confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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“…Variation in this gene has been linked to both substance and depressive disorders (302). Recent genome-wide association studies have linked variants of other genes with mental health disorders such as major depression and this area of research is rapidly expanding (154). The MUSP data available for this study did not permit this type of analysis, but this area may be of future interest, particularly if the involvement during pregnancy can be confirmed.…”

Section: Early Childhoodmentioning

confidence: 98%

“…Certainly genomic studies have identified variants linked to major depression (154). The two disorders may differ in the involvement of the behavioural side of familial mental disorders, but the impact of non-genetic factors appears strongest in childhood.…”

Section: Maternal Depression and Anxietymentioning

confidence: 99%

“…Recent developments in molecular approaches show promise for this issue. Genome wide association studies (GWAS) can be used to link novel DNA variations (polymorphisms) to cases of substance use or mental health disorders, opening up new areas of investigation (154). This field has expanded hugely in the wake of large consortia which pool case data and DNA screening results.…”

Section: Directions For Future Researchmentioning

confidence: 99%

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Comorbid alcohol and mental health disorders: a longitudinal analysis of development to young adulthood

Salom¹

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Background:Alcohol is the most widely consumed of the psychoactive substances and was responsible in 2012 for nearly 6% of all global deaths. Disorders of alcohol use are highly comorbid with mental health disorders and create a significant health burden: the two are responsible for 183.9 million DALYs annually. The majority of this burden of disease falls on young adults, and despite the poorer prognosis and more frequent relapse that characterise this condition, information on early life factors associated with its development is limited. Data provided by large scale population studies and reports on clinical samples are valuable but are limited by the lack of prospective measures or cannot be generalised due to sample specificity. Although predictors of alcohol use disorders and mental health disorders have separately been widely studied, their application to comorbidity is not straightforward. Aims:This study has three main aims:1. To describe the prevalence, types and onset of comorbidities of mental health and alcohol use disorders in young Australians; 2. To understand factors from different phases of the life span which may predict the onset of comorbidity or be affected by it, and which may present targets for intervention; and 3. To consider the role of alcohol in the context of illicit substance and mental health comorbidities.In this context, this research program aims to explore factors which may distinguish comorbidity from its constituent disorders. Methods:Data from this study were drawn predominantly from the Mater-University of Queensland Study of Pregnancy (MUSP), a pre-birth linked cohort of mothers and children begun in 1981. The baseline sample of 7223 pregnancies comprising the original cohort was followed for twenty-one years, providing prospective measures of health and related factors for both mother and child. At twenty one years, structured psychiatric interviews of the offspring provided lifetime DSM-IV diagnoses of mental health, alcohol and other substance use disorders. The condition of interest, alcohol and mental health disorders which co-occurred within a 12-month period, was examined in light of important developmental factors ranging from pre-birth to late adolescence, using primarily ii multinomial logistic regression analyses. Additional data from the Healthy Neighbourhoods Study were analysed to examine potential markers of early-emerging co-occurring conditions in pre-adolescent students. Key findings:Comorbid alcohol and mental health disorders are highly prevalent at young adulthood, occurring in 12% of this representative sample. Indicators of this comorbidity may be detected in children as young as 10-14 years old. A number of factors distinguish the risk of comorbidity from that of single disorders. Socio-economic disadvantage derived from the family of origin contributes significantly to the risk of comorbidity, with risk increasing in a dose-response manner for multiple dimensions of disadvantage. Maternal smoking during pregnancy is also implicated, indep...

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“…However, this approach is not optimal because it either ignores LD between markers, or accounts for LD by discarding potentially informative SNPs [70]. Prediction accuracy of complex phenotypes can be improved by methods that jointly estimate the SNP associations to obtain best linear unbiased predictors (BLUP) of the SNP effects within a linear mixed model (LMM) approach [24,199,200].…”

Section: Introductionmentioning

confidence: 99%

The genetic architecture of psychiatric disorders

Maier¹

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The genetic nature of psychiatric disorders was observed by clinicians long before DNA had been identified as the molecule of inheritance. The greatest identified risk factor of many psychiatric disorders still is a positive family history. Until recently this knowledge has not contributed substantially to treatment efforts or to a better understanding of the disease processes because we lacked the necessary genetic data. Advances in genotyping technologies have brought an end to this data shortage which is leading to a better understanding of the genetic architecture of psychiatric disorders. Two patterns started to emerge which were uncommon in earlier studied Mendelian disorders. (i) most of the genetic part of disease risk is conferred by a large number of genetic loci of small effect, and (ii) genetic loci often influence a large number of traits at the same time. While this is true of many traits ("complex" traits), these two phenomena (polygenicity and pleiotropy) are particularly pronounced in psychiatric disorders. This has wide-reaching consequences for the analysis and interpretation of genetic data and provides challenges as well as opportunities. This thesis focuses on two areas in particular: genetic heterogeneity and genetic risk prediction.Genetic heterogeneity in a phenotypically homogenous group describes a situation where different and distinct genetic risk profiles are causing similar symptoms in different people.This can be easily identified under a Mendelian inheritance pattern, but proves to be challenging under polygenicity. The presence of genetic heterogeneity can limit the accuracy of genetic risk prediction.The aim of genetic risk prediction is to use the information that has been gathered on the effects of genetic loci to estimate the genetic liability of an individual to develop a disease.Here, pleiotropy offers an opportunity to increase the accuracy of genetic prediction by leveraging information from multiple diseases at the same time.The aim in this thesis is to describe several projects which center around the two concepts of genetic risk prediction based on multiple traits and of genetic heterogeneity. Chapter 1 sets the scene with an overview of recently developed polygenic methods. Chapter 2 deals with the effects of genetic heterogeneity on heritability estimates and demonstrates how genetic heterogeneity might contribute to the phenomenon of missing heritability, which is 3 the discrepancy between twin study heritability estimates and the variance explained by the sum of individual genetic loci. Chapter 3 addresses the question of whether genotype clustering can detect groups with different genetic risk profiles. Chapter 4 describes the implementation of a multivariate extension to the univariate Best Linear Unbiased Prediction (BLUP) method and its application to five psychiatric traits. Chapters 4 and 5 investigate whether this multivariate BLUP model can be approximated when only summary statistics, not individual level genotype data, are available for the predi...

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Research Review: Polygenic methods and their application to psychiatric traits

Cited by 620 publications

References 129 publications

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Comorbid alcohol and mental health disorders: a longitudinal analysis of development to young adulthood

The genetic architecture of psychiatric disorders

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