Delayed reward discounting, a measure of capacity to delay gratification, is moderately heritable, 12pct, and it tends to increase with age (changing importance of competing environment factors?)

Genomic Basis of Delayed Reward Discounting. Joshua C. Gray et al. Behavioural Processes, March 12 2019. https://doi.org/10.1016/j.beproc.2019.03.006

Highlights
• Delayed reward discounting (DRD) is a measure of capacity to delay gratification.
• DRD is moderately heritable and associated with mental, physical, and social outcomes.
• DRD is a component of Research Domain Criteria and a putative target for treatment.
• The largest GWAS to date yielded a SNP heritability of 12% and one significant SNP.
• Future priorities include GWAS with larger samples and non-European cohorts.

Abstract: Delayed reward discounting (DRD) is a behavioral economic measure of impulsivity, reflecting how rapidly a reward loses value based on its temporal distance. In humans, more impulsive DRD is associated with susceptibility to a number of psychiatric diseases (e.g., addiction, ADHD), health outcomes (e.g., obesity), and lifetime outcomes (e.g., educational attainment). Although the determinants of DRD are both genetic and environmental, this review focuses on its genetic basis. Both rodent studies using inbred strains and human twin studies indicate that DRD is moderately heritable, a conclusion that was further supported by a recent human genome-wide association study (GWAS) that used single nucleotide polymorphisms (SNP) to estimate heritability. The GWAS of DRD also identified genetic correlations with psychiatric diagnoses, health outcomes, and measures of cognitive performance. Future research priorities include rodent studies probing putative genetic mechanisms of DRD and human GWASs using larger samples and non-European cohorts. Continuing to characterize genomic influences on DRD has the potential to yield important biological insights with implications for a variety of medically and socially important outcomes.

Keywords: delayed reward discountingimpulsivitygeneticsgenomics


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1. Introduction
Thepreference for smaller immediate rewards relative to larger delayed rewards is abehavioral economic concept that reflects the capacity to delay gratification(Green et al., 1994). Delayed reward discounting (DRD) is used to measure how rapidly a reward loses its value based on its temporal distance.Thus, greater DRD reflectsa preference for smaller immediate rewardsrather than larger, delayed rewardsand is one form of impulsivity. Meta-analyses show consistent associations between greater DRD and adverse psychiatric outcomes includingsubstance usedisorders, gamblingdisorder, and attention-deficit/hyperactivity disorder (ADHD) (Amlung et al., 2016a; Jackson &MacKillop, 2016; MacKillop et al., 2011). In terms ofnon-psychiatric healthoutcomes, greater DRD is positively associated withobesity (Amlung et al., 2016b),and negatively associated withglycemic adherence in type 2 diabetes (Lebeau et al., 2016; Reach et al., 2011), obtaining preventative medical care(e.g., flu shots, breast and prostate exams; (Bradford, 2010)), and seatbelt use (Bradford et al., 2014). Finally, even afterattempting to control forparental income andcognitive ability, DRD is negatively associatedwithlifetime outcomes including educational attainment, income, and employment (Golsteyn et al., 2014). Individualswith high DRDappear to be less thoughtful of their future selves, which leads to increased risks for a multitude of deleterious mental, physical, and social outcomes.As such, DRD has been proposed as a target for treatment (Gray &MacKillop, 2015; Lowe et al., 2018; Sheffer et al., 2018)and is one component of theResearch Domain Criteria (RDoC) (Lempert et al., 2018), a National Institute of Mental Health (NIMH) initiative that emphasizes basic dimensions of functioning that span the full range of human behavior from normal to abnormal.Thismini-review will highlight current research relating to the genetic basis of DRD, including data from animal models. We begin with a summary of DRD measurement in humans and nonhuman animals, followed by a review offindings fromheritability and genome-wide association studies (GWASs).We conclude our review by identifying promising future research directions. We will not review the many candidate gene studies that have been conducted on this topic, in part because of the consistent difficulty in replicating candidate loci for complex traits (Chabris et al., 2012; Farrell et al., 2015; Hart et al., 2013), and because candidate genes for DRD have been summarized in two of our recent publications (MacKillop et al., 2019; Sanchez-Roige et al., 2018). Like all psychological traits,DRDis influenced by environmental and genetic factors and presumably also their many interactions. With regard to environmental influences, research indicates that child maltreatment (Oshri et al., 2018a, 2018b), trauma (van den Berk-Clark et al., 2018), and substance use (Mendez et al., 2010; Mitchell etal., 2014; Setlow et al., 2009; Simon et al., 2007)appear to increase levels of DRD. While no-well powered studies have investigated gene-by-environment interactionsrelevant to DRD, it is likely that certain environmental exposures modulate DRDin a genotype-specific manner. Thus, while this mini-review is focused on the genetic basis of DRD, research seeking to understand environmental and gene-by-environment interactions also represent important linesof inquiry.2. Delayed Reward DiscountingMeasurementDRDis typicallyassessed by providing organisms with a choice betweensmaller immediate and larger delayed rewards. In humans, these rewards are usually choices between smaller amounts ofmoneytoday versus larger amounts of money after a delay, though food and drugs have been in place of money(Green and Lawyer, 2014; Odum and Rainaud, 2003; Robertson and Rasmussen, 2018). For example, one of the most widely-used measures, theMonetary Choice Questionnaire (MCQ), consists of 27 questions such as“Would you rather have $24 today or $35 in 29 days?”(Gray et al., 2016; Kirby et al., 1999). Althoughthe rewards are typically hypothetical rather than real, this does not appear to impact responding (Madden et al., 2003; Matusiewicz et al., 2013; Robertson &Rasmussen, 2018). Inanimals such as pigeons androdents, DRD is typicallyassessedusing delayed food or water rewardsand the animals always receive the rewards associated with their choice(Isles et al., 2004; Mazur, 1987; Mitchell, 2014; Richards et al., 2013). In both humans and non-human species, organisms typically devalue delayed rewards in a nonlinear fashion, modeled as ahyperbolicfunction (Vanderveldt et al., 2016). The extent ofDRDcan be quantified in several ways(Myerson et al., 2014),such ascalculatingthe slope of the hyperbolic discounting function (k)ormodel-free methods such asarea under the curveand immediatechoice ratio(Green &Myerson, 2004; Myerson et al., 2001). Figure 1 shows two prototypic hyperbolic demand curvesin humans with differing slopes(more impulsive k= .1, less impulsive k= .01)thatexhibit the discounted subjective value of $100 delayed from 1 day to 1 year. For example, at60 days, $100 is equal in subjective value to $62 today for the less impulsive profileand $14 todayfor the more impulsive profile.Although there are many parallels between the DRD models used with humans and laboratory animals, there are also several notable differences that may affect generalizability across species(for an in depth discussion see Vanderveldt et al., 2016). First, in humans there is a well-documented magnitude effect, whereby humansdiscount small, delayed rewards more steeply than larger delayed rewards. This effect has been shown across reward types including money (Johnson and Bickel, 2002; Madden et al., 2003), food (Odum et al., 2006), and liquid rewards (Jimura et al., 2009). However, the magnitudeeffect has not been consistently observed in nonhuman animals (e.g., Green et al., 2004; Richards et al., 1997). Second, the time frame of the procedures, and presumably the time frame for self-control, differs in humans and laboratory animals. In the animal procedures the delays are in seconds or minutes whereas in most humanprocedures the delays are days to months. Moreover, in the animal procedures,the delays are experienced directly and relate to their immediate thirst or hunger, whereas in humans the delays are communicated by instructionsand typically involve a secondary reinforcer (money) (de Wit et al., 2018). Nonetheless, both humans and laboratory animalsdiscount delayed rewardsin an orderly manner, suggesting a fundamental behavioral homology.3. HeritabilityTheheritability of DRD has been examined in both humans and rodents. In humans, studies with monozygotic and dizygotic adolescent twins provide evidence ofrobust heritability, whichtends to increase through development (i.e. 12 years old (yo) [30%] and 14 yo [51%], (Anokhin et al., 2011); 16 yo [35-46%], 17 yo [47-51%], and 18 yo [55-62%] (Anokhin et al., 2015; Isen et al., 2014; Sparks et al., 2014)). The increase ingenetic influence on DRD throughout developmentmay reflect the changing importance of competing environmental factors and the maturation of the prefrontal cortex in adolescence (Argyriou et al., 2018), a critical region for DRD (Wesley &Bickel, 2014). In mice and rats, a significant proportion ofthe variance in DRD can be attributed tobetween-strain versus within-strain differences(16-50%), which is analogous to the twin model design (Anderson &Woolverton, 2005; Isles et al., 2004; Madden et al., 2008; Richards et al., 1997; Stein et al., 2012; Wilhelm and Mitchell, 2009).The lowest estimate (16%) came from the only study with mice conducted to date (Isles et al., 2004), whereas estimates of heritability in ratsweremuchhigher (40-50%) (Richards et al., 2013; Wilhelm and Mitchell, 2009). However,comparisons across strains of rodents have some limitations.First, strainsweresometimes obtainedfrom different vendors and thus genotype and the different environment of each vendor facility are confounded. Second, studies vary with regard totraining procedure, type of reinforcer (e.g., condensed milk, water), delay range (e.g., 8 vs. 16 seconds maximum delay), number of sessions,and dependent variable (e.g., ratio of delayed choices, AUC, k).On balance, findings from both humans and rodents suggest that DRD is a moderately heritable trait, although the variability in estimates suggests significantmoderators of its heritability. 4. Genome-wide Association StudiesAGWAS is a study of a set of genetic variants sampled across the whole genome to identify polymorphismsassociated with a trait (Visscher et al., 2017). The primary goal of GWAS is to better understand the biology of the trait. Because millions of variants are tested, a stringent significance testing threshold must be employed. It is generally accepted that the significance threshold for any single polymorphism is p< 5 x 10-8. This threshold accounts foran estimated1 million independent tests,and variantsbeyond this threshold tend to replicate (McCarthy et al., 2008; Visscher et al., 2017).Over the past decade, it has become clear that for virtually all common traits, associations tend to be numerous small-effect variants spread across most of the genome, in or near genes that have no obvious biological connection to the trait (e.g., Boyle et al., 2017). Nonetheless, GWASsare thought to yield new insights into the biology of complex traits (Visscher et al., 2017)and ultimately facilitate the discovery ofnovel treatments (Cook et al., 2014; Nelson et al., 2015). To date, two GWASshave been conducted on DRD. Thefirst was conducted incollaboration with thegenetics company 23andMe, Inc., and included23,217 adults of European ancestry(Sanchez-Roige et al., 2018). This study foundsingle nucleotide polymorphism (SNP)-basedheritability of DRD of 12.2%.This SNP-basedheritability is lower than heritability estimates obtained using humantwinsand rodent inbred strains for a number of reasons, includingthat the SNP-basedheritability is an underestimation due to the absence of rare variants(Marouli et al., 2017; Yang et al., 2015),and that pedigreeestimates are inflated due tosharedenvironmental and non-additivegenetic effects (Polderman et al., 2015). In Sanchez-Roige et al., (2018), one SNP, rs6528024,which is located in an intron of the gene GPM6B(Neuronal Membrane Glycoprotein M6B), reached genome-wide significance (p=2.40 × 10-8). This association was supported by an independent cohort of 928 participants(meta-analysis p= 1.44 × 10-8). GPM6Bencodes a protein thatisinvolvedin the internalization of the serotonin transporter and has been implicated in prepulse inhibition and altered response to the 5-HT2A/C agonist DOI in mice (Dere et al., 2015; Fjorback et al., 2009).A large body of research has explored the relationship between serotonergic functioning and DRD; the findings are inconsistent and have primarily relied on rodentmodels. For example, there is some evidence thatserotonin may be more related to increasedconfidence in reward delivery thanto increasedcapacity to wait for a delayed reward (Dalley and Ersche, 2019; Miyazaki et al., 2018). In humans, GPM6Bexpression is downregulated in the brains of depressed suicide victims (Fuchsova et al., 2015)and DRD has been linked to suicide attempts with a pooled odds ratio = 3.14 (95%confidence interval: 1.48-6.67)(Liu et al., 2017). The link between DRD and suicidalityis further supported by genetic correlations identified in the study bySanchez-Roige et al (2018), which foundpositive genetic correlations between DRD and major depression andneuroticismas well as smoking behaviors, ADHD, BMI, and negative associations with years of education and childhood IQ. Thesecond DRD GWASused a sample of986 healthy young adults of European ancestry (MacKillop et al., 2019). That study identifieda genome-wide significant variant (p=2.8x 10-8), rs13395777, on chromosome 2, anassociation that was not observed in the 23andMe cohort(p = .45).There are twomostlikely explanations for this failure to replicate. The finding may have been a false positive, which would explain why it was not detected in a cohort that was ~25x larger. Alternatively,the smaller study was comprised of young adultsand required low levels of substance use, whereas the larger study includeda wider age range, resulting in substantially higher mean age and income,and allowed for psychopathology.5. Future DirectionsDRDis a moderately heritable phenotype that is both phenotypically and genetically associated with an array of negative psychological, cognitive,and health outcomes. The largest GWAS to dateidentified asinglelocus that was associated with DRDand showed that genetic predisposition to high DRD is positively genetically correlated with many of the negative outcomes that have been previously associated with higher DRD. Future studies will be required to further define the geneticbasis of DRD. We are currentlyusing rodents with mutations in GPM6Bto examine DRD and related behavioral traits.We are also continuing to increase the sample size for future GWASsof DRD, which may allow us to identify additional loci (Marouli et al., 2017; Visscher et al., 2017). Another future direction may beto studydiverse ancestral groups,expanding current data from individuals ofEuropean ancestry(Duncan et al., 2018; Locke et al., 2015). Additionally, it will be important to further parse causality betweenDRD and associated outcomes (e.g., addiction, years of education) using methods such as longitudinal designsand Mendelian randomization (Burgesset al., 2015; Grant and Chamberlain, 2014). Finally, DRD is only one element of impulsivity, which is a broader construct that appears to comprise three broad and generally independent domains(MacKillop et al., 2016). Thus, understanding the genetics of impulsivity will also require exploration of othermeasures of impulsivity (e.g., response inhibitionand impulsive personality traits;Gray et al., 2018; Sanchez-Roige et al., 2019; Weafer et al., 2017).

6.  . ConclusionDRDis a heritable trait that can be assessedquickly and reliably both in person and over the internet (Koffarnus &Bickel, 2014; Sanchez-Roige et al., 2018; MacKillop et al., 2018), and influences a variety of health-related outcomes. Although at an early stage, GWASshave begun to identify loci and genes that influence variability in DRD, setting the stage for a deeper understanding of itsmolecular, cellular and circuit-level bases,and perhaps ultimately informing the treatment of psychiatric disorders and other conditions to which it confers risk.

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