PERSONALITY PROCESSES AND INDIVIDUAL DIFFERENCESAn Alternative to the Search for Single Polymorphisms:Toward Molecular Personality Scales for the Five-Factor ModelRobert R. McCrae, Matthew Scally,and Antonio TerraccianoNational Institute on Aging, National Institutes of Health,U.S. Department of Health and Human ServicesGonc¸alo R. AbecasisUniversity of MichiganPaul T. Costa, Jr.National Institute on Aging, National Institutes of Health, U.S. Department of Health and Human ServicesThere is growing evidence that personality traits are affected by many genes, all of which have very smalleffects. As an alternative to the largely unsuccessful search for individual polymorphisms associated withpersonality traits, the authors identified large sets of potentially related single nucleotide polymorphisms(SNPs) and summed them to form molecular personality scales (MPSs) with from 4 to 2,497 SNPs.Scales were derived from two thirds of a large (N ⫽ 3,972) sample of individuals from Sardinia whocompleted the Revised NEO Personality Inventory (P. T. Costa, Jr., & R. R. McCrae, 1992) and wereassessed in a genomewide association scan. When MPSs were correlated with the phenotype in theremaining one third of the sample, very small but significant associations were found for 4 of the 5epersonality factors when the longest scales were examined. These data suggest that MPSs for Neuroti-cism, Openness to Experience, Agreeableness, and Conscientiousness (but not Extraversion) containgenetic information that can be refined in future studies, and the procedures described here should beapplicable to other quantitative traits.Keywords: genome-wide association study, personality assessment, founder effect, five-factor model,NEO-PI-RThe five-factor model (FFM; Digman, 1990) is a classificationof personality traits into five broad dimensions or factors, usuallycalled Neuroticism, Extraversion, Openness to Experience, Agree-ableness, and Conscientiousness. The FFM structure subsumesmost of the traits in natural language and in the systems developedby psychologists, and it appears to be universal, having beenreplicated in over 50 cultures (McCrae et al., 2005). A likelyreason for the universality of the FFM is that the structure has itsroots in genetic factors shared by all human beings (Yamagata etal., 2006). This article describes a new approach to uncovering themolecular genetic basis of personality traits; although the resultsare only a first step in that direction, the method and its rationalemay be of value in moving forward in this challenging area.The heritability of personality traits is well established frombehavior genetic studies (Bouchard & Loehlin, 2001), and since1996 (Benjamin et al., 1996; Lesch et al., 1996), there has beenintense interest in discovering the relevant genes. The initial ap-proach was to identify candidate genes known to be involved inneurotransmission and relate allele differences on these genes toassessed trait levels. Some of these findings have been widelypublicized, and only readers familiar with the whole literature onthe molecular genetics of personality—which is replete with nullfindings (e.g., Vandenbergh, Zonderman, Wang, Uhl, & Costa,1997)—are aware that little, if anything, has been firmly estab-lished.For example, one of the most prominent candidate genes is theserotonin transporter (5-HTT), which reuptakes serotonin fromsynapses and is the site of action of selective serotonin reuptakeRobert R. McCrae, Matthew Scally, Antonio Terracciano, and Paul T.Costa, Jr., Laboratory of Personality and Cognition, National Institute onAging, National Institutes of Health (NIH), U.S. Department of Health andHuman Services, Baltimore, Maryland; Gonc¸alo R. Abecasis, Departmentof Biostatistics, Center for Statistical Genetics, University of Michigan.Robert R. McCrae is now at 809 Evesham Avenue, Baltimore, MD21212. Paul T. Costa, Jr., is now at the Department of Mental Health, JohnsHopkins Bloomberg School of Public Health.This research was supported entirely by the Intramural Research Pro-gram, NIH, National Institute on Aging. Robert R. McCrae and Paul T.Costa, Jr. receive royalties from the Revised NEO Personality Inventory.We thank Jason Thayer and Nicholas Patriciu for assistance in analyses.We also express our thanks to the participants and our collaborators in theSardiNIA project.Correspondence concerning this article should be addressed to Paul T.Costa, Jr., Department of Mental Health, Johns Hopkins Bloomberg Schoolof Public Health, Room 852, Hampton House, 624 North Broadway,Baltimore, MD 21205. E-mail: [email protected] of Personality and Social Psychology, 2010, Vol. 99, No. 6, 1014 –1024In the public domain DOI: 10.1037/a00209641014inhibitors (SSRI antidepressants). Lesch and colleagues (1996)reported that a polymorphism in the promoter region of 5-HTT(5-HTTLPR) was associated with Neuroticism scores. They esti-mated that the polymorphism accounted for 3%– 4% of total vari-ance and 7%–9% of the heritable variance of anxiety-relatedpersonality traits in their sample of 505 individuals. Such relativelylarge effects should be easily replicated, yet several studies havefailed to find an association of 5-HTTLPR with Neuroticism-related traits. Meta-analyses of up to 60 samples (Munafo` et al.,2009; Schinka, Busch, & Robichaux-Keene, 2004; Sen, Burmeis-ter, & Ghosh, 2004), and three large studies that included roughly4,000 participants each (Munafo` et al., 2009; Terracciano et al.,2009; Willis-Owen et al., 2005), indicate that there is in fact noassociation between the 5-HTTLPR and Neuroticism-related traits.Unfortunately, similar failures to replicate have been observedfor other candidate genes. The Val66Met variant of the brain-derived neurotrophic factor (BDNF), for example, appeared to berelated to Neuroticism in an earlier report based on 441 partici-pants (Sen et al., 2003), but a recent meta-analysis (N ⫽ 15,251)found that Val66Met was unrelated to Neuroticism (Terracciano,Tanaka, et al., 2010). Genes (such as APO-E4) are known topredispose individuals to illnesses (such as Alzheimer’s disease)that alter personality traits (Siegler et al., 1991), but we are notaware of any gene or SNP that is consistently related to a person-ality trait in healthy individuals across a range of samples. Atpresent, the claim that personality traits have a genetic basis restschiefly on behavior genetic studies.This failure to find consistent effects might be