What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn

Kendler, Kenneth S.

doi:10.1038/mp.2013.50

Cited by 168 publications

(98 citation statements)

References 77 publications

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“…Environmental psychosocial stressors are important in pathogenesis, because episodes are usually preceded by adverse life events, and early childhood experiences of physical and emotional abuse and parental neglect are important vulnerability factors (3,4). Genetic vulnerability is significant with a heritability of about 35% (5).…”

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confidence: 99%

“…One way to improve sensitivity is to take a system-based approach: if galanin is mechanistically involved in depression, genetic variation in the peptide and its receptors should exert similar influences, despite the fact the genes are located on entirely different chromosomes without linkage disequilibrium (LD) and with a low probability of randomly similar effects. Others have argued that improved sensitivity will come from deeper phenotyping (56) and characterization of environmental factors (3,4,57), because neither genetic nor environmental factors can be identified in isolation, if they modify each other's action to a high degree. Combining these two approaches, and in view of its preclinical properties, we predicted that variation in galanin genes would strongly interact with environmental stress in determining depression vulnerability.…”

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confidence: 99%

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Brain galanin system genes interact with life stresses in depression-related phenotypes

Juhász

Hullám

Eszlári

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.galanin receptors | mood disorders | network-based analysis | neurogenesis | transmitter coexistence M ajor depressive disorder (MDD) is a common and serious disease afflicting more women than men, and a leading cause of disability worldwide, associated with much suffering and major costs for society (1, 2). Environmental psychosocial stressors are important in pathogenesis, because episodes are usually preceded by adverse life events, and early childhood experiences of physical and emotional abuse and parental neglect are important vulnerability factors (3, 4). Genetic vulnerability is significant with a heritability of about 35% (5). We remain ignorant about the brain processes that translate these genetic and environmental influences into depressive symptoms or risk. A major clue is that effective antidepressant drugs act directly or indirectly to enhance neurotransmission in serotonin (5-HT) and norepinephrine monoamine pathways, proving the monoamine hypothesis of depression (6-8). Many other candidate mechanisms have been identified in anatomical, pharmacological, and behavioral studies of stress in rodents. However, the demonstration of stateor trait-related abnormalities in human monoamine or other neural systems remains frustratingly elusive, despite modern brain-imaging methods. To determine whether the neuropeptide galanin has a role in depression, we used a unique Bayesian systems-based analysis to dissect out the influ...

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confidence: 99%

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confidence: 99%

Brain galanin system genes interact with life stresses in depression-related phenotypes

Juhász

Hullám

Eszlári

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent new mathematical methods enable the computation of the amount of risk of illness contingent on SNPs, which are usually determined by GWAS studies (Kendler, 2013). A corresponding study showed that a 41% risk for bipolar I disorder is defined by the GWAS data of Wellcome Trust Case Control Consortium (Lee et al, 2011).…”

Section: Geneticsmentioning

confidence: 99%

Toward stratified treatments for bipolar disorders

Hasler¹,

Wolf²

2015

European Neuropsychopharmacology

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“…These estimates pointed to a large genetic component of many psychiatric traits [1], implying that it would be worthwhile to study this component in greater detail [2,3]. This has become possible in the last fifteen years through the reduction in the cost of genotyping technologies.…”

Section: Introductionmentioning

confidence: 99%

“…Psychiatry uses carefully drafted disease classifications, which are in turn based on various symptom configurations, but it is an open question if the separations imposed by these classifications are mirrored in a similar structure on the genetic level [2,5]. If that is not the case, our current diagnostic criteria are not perfectly aligned with underlying biology, and what we classify as one disease might in fact be genetically distinct groups of diseases.…”

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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What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn

Cited by 168 publications

References 77 publications

Brain galanin system genes interact with life stresses in depression-related phenotypes

Brain galanin system genes interact with life stresses in depression-related phenotypes

Toward stratified treatments for bipolar disorders

The genetic architecture of psychiatric disorders

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