Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Wray, Naomi R.; Pergadia, Michele L.; Blackwood, Douglas; Penninx, Brenda W. J. H.; Gordon, Scott D.; Nyholt, Dale R.; Ripke, Stephan; MacIntyre, Donald J.; McGhee, Kevin A.; Maclean, Alan; Smit, Johannes H.; Hottenga, Jouke‐Jan; Willemsen, Gonneke; Middeldorp, Christel M.; Geus, Eco J. C. de; Lewis, Cathryn M.; McGuffin, Peter; Hickie, Ian B.; Oord, Edwin J. C. G. van den; Liu, J. Z.; MacGregor, Stuart; McEvoy, Brian; Byrne, Enda M.; Medland, Sarah E.; Statham, Dixie J.; Henders, Anjali K.; Heath, Andrew C.; Montgomery, Grant W.; Martin, Nicholas G.; Boomsma, Dorret I.; Madden, Pamela A. F.; Sullivan, Patrick F.

doi:10.1038/mp.2010.109

Cited by 396 publications

(349 citation statements)

References 55 publications

(71 reference statements)

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“…Heritability rates for depression are estimated between 40% and 50%, suggesting a substantive genetic contribution to risk for depression (Lohoff, 2010). Further, specific candidate genes have been investigated, including the serotonin transporter gene (Caspi, Hariri, Holmes, Uher, & Moffitt, 2010), the Brain-Derived Neurotrophic Factor (BDNF) gene (Hashimoto, 2010) and the Tryptophan Hydroxylase gene (Zill, Baghai & Ackenheil, 2004; for review see, Wray et al, 2012). Diathesis-stress theories develop the gene x environment model suggesting that stress interacts with a potential predisposition leading to psychopathology (Monroe & Reid, 2009;Monroe & Simons, 1991).…”

Section: Example 4: Individual Differences In Contingency Learning Anmentioning

confidence: 99%

Individual differences are more than a gene × environment interaction: The role of learning.

Byrom

Murphy

2018

Journal of Experimental Psychology: Animal Learning and Cogniti

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Individual differences in behavior are understood generally as arising from an interaction between genes and environment, omitting a crucial component. The literature on animal and human learning suggests the need to posit principles of learning to explain our differences. One of the challenges for the advancement of the field has been to establish how general principles of learning can explain the almost infinite variation in behavior. We present a case that: 1) individual differences in behavior emerge, in part, from principles of learning; 2) associations provide a descriptive mechanism for understanding the contribution of experience to behavior; 3) learning theories explain dissociable aspects of behavior. We use four examples from the field of learning to illustrate the importance of involving psychology, and associative theory in particular, in the analysis of individual differences, these are; i) fear learning, ii) behavior directed to cues for outcomes (i.e., sign-and goaltracking), iii) stimulus learning related to attention, and iv) human causal learning. Individual Differences 3A goal of research into learning is to characterize how behavior changes with experience within and across species. Thorndike's (1898) Law of Effect was an early attempt to characterize the effect of experience on behavior. In offering a general law of how experience contributes to behavior, Thorndike was also giving an account of how an individual becomes unique.The classic example of Thorndike's method involved cats and an apparatus known as a puzzle box (Thorndike, 1898). The box was a rudimentary cage with latches and gates to afford escape. The cats' dislike of confined space provided a natural motivation to engage in behaviors that might serendipitously lead to release. Thorndike observed that the cats made many false starts but eventually made a response that enabled escape. With repeated exposure to the box, latency to escape decreased. The Law of Effect stated that behaviors preceding any form of 'satisfaction' (e.g., escape) would be reinforced and made more likely on subsequent trials. However, rather than considering this principle as limiting an animal's flexibility to learn, the law only restricts the conditions for learning. Consider that outside the lab, different humans can successfully complete a motivated goal in different ways. They may behave differently but the same Law of Effect strengthens their behaviors.The goals of this paper are to present the case for the individual differences approach to learning theory. We will argue that (1) learning mediates the influence of genes and environment on behavior and (2) there is complexity, to be explored, within models of learning that can account for diversity in learning. Specifically, we suggest that while genes and environment may contribute to the development of differences in learning, that an individual's phenotype interacts with experience and the memories of experience to further cause individual differences. As such, the study of individual diff...

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Section: Example 4: Individual Differences In Contingency Learning Anmentioning

confidence: 99%

Individual differences are more than a gene × environment interaction: The role of learning.

Byrom

Murphy

2018

Journal of Experimental Psychology: Animal Learning and Cogniti

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“…Nominally significant associations will include many false-positives. Nevertheless it is noteworthy that SNPs in the gene for galanin (GAL) were among the top 10 genes whose variation was associated with MDD in a recent GWAS (55). 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.…”

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confidence: 99%

“…Genetic studies have the potential to identify molecular mechanisms of MDD vulnerability (53), but even mega-and meta-analyses of large genome-wide association studies (GWAS) have not identified genetic variants associated with MDD that survive genome-wide statistical correction (54,55). Nominally significant associations will include many false-positives.…”

mentioning

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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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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“…With recent advances in technology that enhance accessibility to genetic sequencing and analysis, studies have taken off in multiple directions to investigate implications of genetics and other biomarkers in relation to personalized assessment and treatment of depression. Although a recent genome-wide association (GWA) study of 2431 MDD patients and 3673 controls failed to identify a single genetic mechanism or pattern that predicts MDD diagnosis [10], research has begun to examine the relationships between genes and treatment efficacy, indicating possibilities for personalized care. Table 1 provides a summary of recently identified candidate genes and their proposed functional roles.…”

Section: Biological Factors: Genetics Biomarkers and Medicationsmentioning

confidence: 99%

Personalized assessment and treatment of depression

Fisher

Bosley

2015

Current Opinion in Psychology

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Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Cited by 396 publications

References 55 publications

Individual differences are more than a gene × environment interaction: The role of learning.

Individual differences are more than a gene × environment interaction: The role of learning.

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

Personalized assessment and treatment of depression

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