From DNA to Social Cognition

Richard Ebstein, Simone Shamay-Tsoory, Soo Hong Chew, Richard Ebstein, Simone Shamay-Tsoory, Soo Hong Chew

• Publisher: Wiley-Blackwell
• Year: 2011
• Print ISBN: 9780470543962
• eBook ISBN: 9781118101797
• Edition: 1
• Topic: Psychology
• Subtopic: Social Psychology
• Index: Psychology

Decision-making is an integral part of our daily lives. Researchers seek a complete understanding of the decision-making process, including the biological and social basis and the impact of our decisions. From DNA to Social Cognition fills a gap in the literature that brings together the methods, perspectives, and knowledge of the geneticists, neuroscientists, economists, and psychologists that are integral to this field of research. The editors' unique expertise ensures an integrated and complete compilation of materials that will prove useful to researchers and scientists interested in social cognition and decision-making.

PART 1: EMPATHY: NEURAL BASES AND GENETIC CORRELATES

1.1

GENES RELATED TO AUTISTIC TRAITS AND EMPATHY

BHISMADEV CHAKRABARTI^1,2 AND SIMON BARON-COHEN²

¹Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, U.K.

²Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, U.K

Empathy is the glue that binds human society together. It is the ability to understand one’s own and others’ mental states and to respond to these appropriately (Baron-Cohen & Wheelwright, 2004). It is of particular interest to study empathy in relation to autism spectrum conditions (ASC) because these are marked by atypical social behavior. Recent years have witnessed significant advances in understanding the neurobiology of empathy and its individual differences (Chakrabarti & Baron-Cohen, 2006; Singer & Lamm, 2009). Independently, human molecular gen­etics has made enormous advances in the past decade, both in delineating the role of specific genes as well as in making it possible to identify a large number of sequence variations (polymorphisms) in the whole human genome at once. It is therefore timely to take a multilevel perspective in the study of empathy and social cognition, encompassing all stages from genes to cognition. In this chapter, we provide a brief overview of genetic studies of empathy and other trait measures of ASC. We then describe a recent study from our group, using dimensional phenotypic measures of empathy and autistic traits. Finally, we discuss some initial studies that relate genetic variation to “intermediate phenotypes” (also known as endophenotypes) relevant to ASC.

ASC entail a disability in social and communication development, alongside unusually narrow interests (“obsessions”) and repetitive behavior (APA, 1987; ICD-10, 1994). ASC have a genetic basis, which is indicated by signficantly higher concordance rates in monozygotic (MZ) than in dizygotic (DZ) twins, and with heritability estimates of more then 90% (Bailey et al., 1995; Folstein & Rutter, 1977). During the last three decades, several strategies have been used to discover genes related to ASC. A common feature in most of these studies has been the use of clinical diagnosis of ASC as a categorical phenotype. In these studies, people with a diagnosis of ASC are compared with a group of people without a clinical diagnosis, matched on a variety of measures. This approach has implicated multiple genes, along with environmental (Wagner, Reuhl, Cheh, McRae, & Halladay, 2006) and epigenetic factors (Crespi & Badcock, 2008; Nagarajan et al., 2008). Mixed evidence from genome-wide linkage studies of samples that do not differentiate between classic (low-functioning) autism and Asperger Syndrome (AS) have found linkage peaks in nearly all chromosomes (Abrahams & Geschwind, 2008).

Genome-wide association studies (GWAs) are a more recent development, and they use oligonucleotide microarrays that allow for simultaneous genotyping of common polymorphisms from nearly all known human genes. The initial GWAs on autism, using the traditional case-control design, have found significantly associated polymorphisms in genes located on multiple chromosomes (AGPC, 2007; Wang et al., 2009). In addition, recent findings suggest that rare de novo copy number variations (CNVs) can potentially account for up to 10–24% of cases in families that have only one child with ASC (Jacquemont et al., 2006; Pinto et al., 2010; Sebat et al., 2007). In sum, case-control genetic studies of an ASC suggest that:

a) ASC is an oligogenic condition (i.e., it is unlikely that there will be a single gene whose malfunction will explain all features of this condition).

b) Both rare as well as common sequence variants (single nucleotide polymorphisms [SNPs] and CNVs) are associated with this condition (Arking et al., 2008; Corvin, Craddock, & Sullivan, 2010; Glessner et al., 2009; Pinto et al., 2010; Wang et al., 2009).

Although genotyping common and rare sequence variants of the whole human genome has become a routine procedure during the last few years, most studies have continued to use the classic case-control design. This poses some potential problems, particularly for autism research. The heterogeneity within ASC is not captured in this design, as most of these studies group people with classic autism together with those on the broader spectrum (having a diagnosis of High-Functioning Autism [HFA] or AS). This raises the possibility of potential confounds resulting from factors such as language delay, below average IQ (as observed in classic autism but not in AS) or co-occurring (a term we prefer to the more medical term “comorbid”, for obvious reasons) conditions such as epilepsy and hyperactivity. In addition, a commonly used measure for verifying a current clinical diagnosis of autism (e.g., the Autism Diagnostic Observation Schedule [ADOS] (Lord et al., 1989) is

a) Optimized for diagnosing classic autism, and not AS/HFA and

b) Does not include one key dimension of the autistic symptomatology (repetitive behavior) in its final scoring algorithm, both of which could result in a biased sampling within the clinical cohorts.

In view of the heterogeneity within ASC, and given the existence of the broader autism phenotype (BAP) (Piven, Palmer, Jacobi, Childress, & Arndt, 1997) or subthreshold instances of ASC, an emerging consensus in autism phenotypic studies suggests that autistic traits are distributed on a continuum not just within clinic samples but right across the general population. The Autism Spectrum Quotient (Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001) is one such trait measure that captures the population variability in autistic traits in both social and repetitive behavior domains. Other trait measures such as the Empathy Quotient (EQ) (Baron-Cohen & Wheelwright, 2004) and the Social Responsiveness Scale (SRS) (Constantino, Przybeck, Friesen, & Todd, 2000) provide a dimensional measure of the social functioning in the general population, and people with ASC tend to cluster toward the low end of the score distribution.

Empathy has been a focus of genetic study for several decades. A standard approach so far has been to test for heritability of “trait empathy” (i.e., stable individual differences in empathy) or other aspects of social behavior by comparing MZ and DZ twins. Nearly all of these studies have shown a greater correlation of empathy measures in MZ compared with DZ twins, suggesting a genetic basis for trait empathy (Davis, Luce, & Kraus, 1994; Loehlin & Nichols, 1976; Matthews, Batson, Horn, & Rosenman, 1981) as measured indirectly using the Questionnaire Measure of Emotional Empathy (QMEE) (Mehrabian & Epstein, 1972). Rushton, Fulker, Neale, Nias, and Eysenck (1986), in a large-scale twin study in humans, suggested a large heritability estimate of 68% for emotional empathy. Other twin studies, particularly in children, have used behavioral observation paradigms of empathy in a laboratory situation. These involve simulating scripted situations (e.g., the experimenter tripping on a chair, or the mother of the child getting her finger caught while closing a suitcase), while video-recording the child’s reactions. A study of 14- and 20-month-old twins using this paradigm confirmed a genetic contribution to empathic concern (Zahn-Waxler, Radke-Yarrow, Wagner, & Chapman, 1992). A recent twin study on 409 twin pairs by the same group showed that genetic effects on empathy and prosociality (measured using video-recorded behavior in a laboratory setting) increase with age and that shared environmental effects decrease with age (Knafo, Zahn-Waxler, Van Hulle, Robinson, & Rhee, 2008). Self-reported empathy is one of several trait measures of social behavior. Several other trait and performance measures of social behavior have been studied for genetic contributions (Ebstein, Israel, Chew, Zhong, & Knafo, 2010). Among behavioral phenotypes specifically relevant to ASC, performance on the “Reading the Mind in the Eyes” Test (RMET), shows a strong degree of familiality (Baron-Cohen & Hammer, 1997; Losh & Piven, 2007). Questionnaire measures of social functioning using the SRS (Constantino & Todd, 2000, 2005; Sung et al., 2005) and of autistic traits using the Autism Spectrum Quotient (AQ) (Baron-Cohen et al., 2001) reveal strong familiality (Bishop et al., 2004; Wheelwright, Auyeung, Allison, & Baron-Cohen, 2010) as well as heritability in twin studies (Hoekstra, Bartels, Verweij, & Boomsma, 2007). These studies corroborate findings from the early twin studies in suggesting a genetic underpinning for social behavior relevant to ASC.

Interestingly, most of these phenotypic measures have been studied not just on family relatives but also primarily on the higher functioning end of the autism spectrum (HFA and/or AS). This is in contrast to the large-scale genetic studies, which have primarily tested the “lower functioning” end of the clinical spectrum, focusing on classic autism. This presents a disconnect between advances at the phenotypic and genotypic ends of the sequence from DNA to cognition. This disconnect manifests itself in two potential problems: (1) Possible confounds resulting from genes related to low IQ, language delay, or co-occuring conditions might influence the inferences we can draw from the large-scale case-control studies of ASC; and (2) by treating ASC as a categorical condition, it does not take into account the continuous nature of the distribution of autistic traits in the general population. A small number of pioneering studies have attempted to study the dimensional phenotypes within ASC using linkage and association studies (Campbell, Warren, Sutcliffe, Lee, & Levitt, 2010; Conciatori et al., 2004; Losh, Sullivan, Trembath, & Piven, 2008). We attempted to bridge this disconnect by conducting two parallel candidate gene association studies in our laboratory, which we describe in the next section. The first is of autistic traits (measured using the AQ) and empathy (measured using the EQ) in the general population. The second is of AS, which is marked by social and behavioral impairments and unusually narrow interests, but it is not associated with language or general cognitive delays during development.

A key feature of our studies was in the choice of multiple candidate genes from three groups of genes, defined by gene function. This approach has been used in other conditions (Pharoah, Tyrer, Dunning, Easton, & Ponder, 2007) but not in the study of ASC. Traditionally, genetic association studies of ASC have either studied one or a small number of candidate genes or the whole genome (Losh et al., 2008). We chose 68 candidate genes for these two experiments, derived from three functional categories: (1) sex hormone-related genes; (2) genes involved in neural development and connectivity; and (3) genes involved in social and emotional responsivity (see Table 1.1-1). We searched for common genetic variants (single nucleotide polymorphisms [SNPs]) on the assumption that autistic traits are continuously distributed in the general population so the genetic contributions to individual differences in empathy or autistic traits are likely to be normative variants rather than “disease”-causing mutations. Each of the three functional categories derives from a clear neurocognitive theory of ASC, which will be outlined next.

TABLE 1.1-1. List of all genes included in the association study, along with brief functional roles where known. Genes marked in bold indicate those previously linked to ASC through genetic linkage/association studies.

Reproduced from Chakrabarti et al. (2009)

Neural development and connectivity
NGF, BDNF, NTF3, NTF5, NGFR, NTRK1, NTRK2, NTRK3, TAC1,IGF1,IGF2	Neuronal survival, differentiation and growth.
RAPGEF4	Growth and differentiation of neurons. Mutations associated with classic autism.
VGF	Upregulated directly by NGF and expressed in neuroendocrine cells.
VEGF	Promotes cell growth and migration, especially during angiogenesis and vasculogenesis, often observed during hypoxia. Modulated directly by PTEN.
ARNT2	Neural response to hypoxia
NLGN1,NLGN4...

Table of contents

• Cover
• Title page
• Copyright page
• CONTRIBUTORS
• INTRODUCTION
• PART 1: EMPATHY: NEURAL BASES AND GENETIC CORRELATES
• PART 2: MORAL NEUROSCIENCE AND EMOTION
• PART 3: GENES AND DECISION MAKING
• Index
• Color Plates