1 Egan M.F.

et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. No one today can ignore the genetic approach to cognition and behavior, given the huge achievements of the Human Genome Project ( http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml ). The initial impact of studies of individual differences in genetic polymorphisms, such as the catechol-O-methyl transferase (COMT) gene, and their relationship to such core cognitive concepts as working memory (in this case via its modulation by prefrontal dopamine []) has been immense, catching the imagination of many cognitive neuroscientists. Here is a way, for example, to evaluate the effect of individual differences in neurotransmitter function without the need to administer drugs. Alternatively, possible heterogeneity in behavioral performance or patterns of neural network activation revealed through functional neuroimaging, may be resolved by taking into account genetic factors.

Taken together, the contributions in this special issue address the genetic underpinnings of key aspects of cognition, such as memory, intelligence, reward processing, as well as emotion and personality, in the context of both healthy populations and in key disorders, such as schizophrenia, autism, and addiction. Collectively, the articles discuss evidence from a variety of perspectives and different approaches, including twin, linkage, candidate gene, genome-wide association, imaging genetics, gene × environment interaction, and gene expression studies, providing insight into the strengths and challenges for each approach.

A key insight arising from several articles in this issue is that variations in complex psychological attributes such as intelligence and psychosis are usually likely to be determined by multiple genes, each exerting a small effect. Moreover, it is becoming increasingly clear that, so as to establish valid behavioral–genetic correlations, it is necessary to test large populations, in order to avoid spurious false positive effects arising from the very large number of contributing genes. Finally, the well-known mantra of the importance of ‘gene × environment interaction’ has gained additional complexity from the discovery of effects of imprinted genes and epigenetic factors.

As several articles in this special issue make clear, some of the inspiration for the genetic (and epigenetic) approach to cognition comes from our need to understand better the origin of disorders in mental health. The hope is that by understanding their genetic basis, we will be able to identify the causal molecular pathology of different disorders and capitalize on proteomic approaches for treatments. By paying attention to possible intermediate phenotypes (‘endophenotypes’), which may have a biochemical, neural or even cognitive-behavioral basis, we may be able to bridge the present daunting gap between genes and psychopathology.

Rapid advances in the field of genetics have also raised several ethical and legal questions. In the first article in this issue, Morse discusses one such question: what are the implications of genetic research for the concept of criminal responsibility? Morse explains that the concept of criminal responsibility as determined by law is based on identifying relevant mental states: was there an intention to commit a crime? And did the individual possess knowledge of wrongdoing? Genetic research, on the other hand, is concerned with mechanistic causation, and causation does not currently constitute an excusing condition in law. Unless it can be shown that biological causation is directly responsible for a particular mental state, it cannot be used either as a mitigating factor or an excuse for a criminal act. But one could argue, and some have, that an individual's genetic make-up completely determines behaviour, hence suggesting that the concept of criminal responsibility as defined by law should be completely revised: it is biology, not mental states that matter. However, Morse argues, genetic research (or any other research) has provided no evidence to support the idea that mental states are redundant and do not have a causal role in driving behavior. And denying a critical role for mental states would do away with human motivation to do anything whatsoever, not just a criminal act.

The four review articles that follow address different aspects of cognitive and emotional processes from a genetic perspective. Papassotiropoulos and De Quervain overview the literature on the genetic underpinnings of human episodic memory, discussing the findings of two key approaches: candidate gene studies based on well-established molecular pathways involved in synaptic plasticity and hypothesis-free genome-wide association studies. Although both types of approaches have yielded promising results, much remains to be discovered. Key in achieving progress, the authors argue, is understanding the phenotypic complexity of episodic memory: episodic memory is not one phenotype, and similarity of a phenotype between studies might not be sufficient for replication purposes. Moreover, most studies (both candidate-gene and genome-wide association studies) still perform simple statistics, analyzing genetic variants independently of each other. This approach covers a minor part of the complexity of episodic memory, and new methods are needed to capture the genetic variability of human memory, for instance, through additive or epistatic interactions.

Cognitive ageing affects people's quality of life and predicts dementia and death. Harris and Deary focus on the genetics of cognitive function in healthy aging, and summarize findings across several different approaches in behavioral and molecular genetics. They discuss a number of findings, best established among which is evidence that the ɛ4 haplotype of the apoliprotein E (APOE) gene is positively associated with cognitive ageing trajectories and with cognitive function in elderly individuals. Several other loci might be implicated in cognitive function and decline with age, however, and the authors argue that well-designed longitudinal studies, with long follow up times, are required to determine further genetic influences on cognitive ageing in healthy older individuals.

Munafò and Flint critically review the personality genetics literature, as a case study of the missing heritability problem: as with any other complex trait, the genetic architecture of personality traits, the authors argue, is likely to be the result of several hundreds, if not thousands, of small effect loci, which together nonetheless produce substantial heritability. Early candidate gene studies found positive associations of the serotonin transporter gene (SLC6A4) with measures of neuroticism, and the dopamine D4 receptor gene (DRD4) with novelty seeking. Although follow up candidate gene studies, as well as gene by environment interaction studies, abound, meta-analytic studies suggest that these genes, as well as other candidate genes identified, have a very small effect at best. In fact, a number of recent genome-wide association studies have failed to identify any locus with clear genome-wide significance. Munafò and Flint argue that, in order to achieve progress in this field, it is important to consider issues of power, statistical stringency and independent replication; and to acknowledge that, as with other complex traits, such as blood pressure and height, variation in personality is the outcome of the combined effect of several small effect loci.

In a related contribution, Bevilacqua and Goldman discuss the genetic basis of emotional processing, personality and temperament, focusing on functional variants at five genes: COMT, SLC6A4, neuropeptide Y (NPY), a glucocorticoid receptor-regulating cochaperone of stress proteins (FKBP5) and pituitary adenylate cyclase-activating polypeptide (PACAP), as illustrative of the effects of genes on emotion. They address factors that alter or confound the effects of these genes, especially gene × environment interactions, as emotionality is strongly influenced by exposure to stress. They acknowledge the issues highlighted in Munafò and Flint's contribution—the few genome-wide association studies that have examined the effects on emotion of genes identified in candidate gene studies have indeed failed to yield any significant results for these genes. And they converge with Munafò and Flint on likely explanations (statistical power and the fact that emotionality is likely to be underpinned by several different loci of small effect). However, despite lack of genome-wide significance in the few studies carried out up to now, the authors argue, these genes have large effects on metabolic responses of the brain to emotional stimuli assessed in real time by brain imaging, hence validating the effects of these genes in emotion.

The final four review articles in this issue address the genetic basis of disorders in which cognitive and emotional dysfunctions are a key aspect. Amongst them, autism genetics may be the area where most progress has been achieved, with known genetic causes for 10–20% of the cases. Geschwind discusses the current state of the art in autism genetics, highlighting the fact that autism spectrum disorders (ASD) are both highly heritable but also etiologically heterogeneous. Moreover, he points out that the autism phenotype is broad and overlaps with many other neurodevelopmental disorders. Geschwind reviews research that has identified common and rare gene variants and explains how these findings verify or refute prevailing genetic models of autism. He explains that new approaches, such as gene expression and epigenetics, have provided novel insight into the genetic basis of ASD. This more recent research has suggested that, despite their heterogeneity, the multiple genetic causes of ASD converge on a few biological pathways affected in most individuals with autism.

In the context of psychopathology, Hyde, Bogdan and Hariri discuss recent advances in gene × environment interactions and imaging genetics, two approaches that up to the present have been largely independent. They highlight the key strengths as well as challenges for both strands of research and argue that bridging these two approaches will provide crucial insight into risk factors for psychopathology. They lay out the foundations of an integrated approach, imaging gene × environment interactions, by examining statistical methods for combining the two approaches and by discussing plausible biological mechanisms, such as epigenetics, that can explain the interplay between genes, experience, and the brain. Imaging gene × environment interactions, the authors argue, holds significant promise to elucidate biological mechanisms that underlie the etiology and pathophysiology of psychopathology and for the development of personalized treatment and refined diagnostic criteria.

It is well-established that, in addition to psychotic symptoms, cognitive impairment in schizophrenia is severe. Bilder and colleagues’ contribution addresses our current understanding of the genetic basis of cognitive dysfunction in schizophrenia. They conclude that, despite intense research, little progress has been made up to the present in detecting genetic associations for cognitive impairments in schizophrenia. The authors advocate a specific approach, phenomics, as offering significant promise in this field, by emphasizing the simultaneous study of multiple phenotypes across biological scales. This approach might be particularly fruitful if it is the case that the high heritability of schizophrenia and cognitive impairments is due to large numbers of variants with small effects. Bilder et al. present a new collaborative database, CogGene, to share data on genetic associations with cognitive phenotypes. They show how examining results from this database in parallel with results from a similar database on genetic associations in schizophrenia (SZGene) can provide important insight into the genetic underpinnings of cognitive impairment in schizophrenia.

Abnormalities in reinforcement behaviour (sensitivity to rewards and punishment, inhibitory control and stress-related emotional vulnerability), particularly during adolescence, have been linked to addiction vulnerability. Loth, Carvalho and Schumann examine the genetic basis of inter-individual differences in reinforcement and reward-related processes by focusing on imaging genetic studies. These studies have addressed associations between one or a few candidate polymorphisms and task-related brain activation differences in a few regions of interest, and have revealed effect sizes that manifold exceed the variance typically explained with behavioural traits or cognitive measures. Despite their usefulness, however, results across studies are not always consistent, and the authors advocate strengthening the imaging genetics approach by examining large sample sizes and using longitudinal designs (with repeated testing of the same individuals at different ages).

2 Bouchard T.J.

McGue M. Genetic and environmental influences on human psychological differences. Twin, family and adoption studies have demonstrated that there is a substantial heritable component to all cognitive functions []. The articles in this special issue summarize what is currently known about the genetic underpinnings of these functions and their disorders. At the same time, they highlight just how much there is yet to be discovered in this rapidly advancing field.

Article Info Publication History Identification DOI: https://doi.org/10.1016/j.tics.2011.07.006 Copyright © 2011 Elsevier Ltd. Published by Elsevier Inc. All rights reserved. ScienceDirect Access this article on ScienceDirect