Saturday, August 7, 2010

Bad News for the Genetics of Personality

CREDIT: RYAN SNOOK (from Holden, 2008).


The latest search for genetic variants that underlie differences in personality traits has drawn a blank (Verweij et al., 2010). The researchers conducted a genome-wide association study using personality ratings from Cloninger's temperament scales in a population of 5,117 Australian individuals:
Participants' scores on Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were tested for association with 1,252,387 genetic markers. We also performed gene-based association tests and biological pathway analyses. No genetic variants that significantly contribute to personality variation were identified, while our sample provides over 90% power to detect variants that explain only 1% of the trait variance. This indicates that individual common genetic variants of this size or greater do not contribute to personality trait variation, which has important implications regarding the genetic architecture of personality and the evolutionary mechanisms by which heritable variation is maintained.
But it's still fun and popular for some science writers to assert that personality traits are "hard wired" into our brains, like there's really A Brain Circuit for Bungee Jumping? [thanks for the exciting new info, ScienceNOW.] In reality, some of the major early findings in personality genetics, such as an association between Novelty Seeking and the Dopamine D4 Receptor gene (Benjamin et al., 1996; Ebstein et al., 1996), have failed to replicate (Gelernter et al., 1997; Paterson et al. 1999; Strobel et al., 2002). Fortunately, others writers have pointed out the increasingly obvious difficulties of this endeavor, as did Constance Holden in Parsing the Genetics of Behavior:
For some of us, it's satisfying to attribute social awkwardness to anxiety genes or to think that the driver who cuts off other cars as he zips across lanes is pumped up by the "warrior" gene. Was it a bad dopamine receptor gene that made author Ernest Hemingway prone to depression? Can variations in a vasopressin receptor gene--a key to monogamy in voles--help explain adulterous behavior?

But as scientists are discovering, nailing down the genes that underlie our unique personalities has proven exceedingly difficult. That genes strongly influence how we act is beyond question. Several decades of twin, family, and adoption studies have demonstrated that roughly half of the variation in most behavioral traits can be chalked up to genetics. But identifying the causal chain in single-gene disorders such as Huntington's disease is child's play compared with the challenges of tracking genes contributing to, say, verbal fluency, outgoingness, or spiritual leanings. In fact, says Wendy Johnson, a psychologist at the University of Edinburgh, U.K., understanding genetic mechanisms for personality traits "is one of the biggest mysteries facing the behavioral sciences."

Nonetheless, unscrupulous businesses like My Gene Profile (which offers the "Inborn Talent Genetic Test" for the low low price of $1,397) have capitalized on the public's desire for simple explanations. Now you can find out whether your child has the Split Personality Gene! The Propensity for Teenage Romance Gene! The Self Detoxifying Gene!

Returning to the current study, the authors cast a genome-wide net to find genetic variants related to the four dimensions of temperament identified by Cloninger in his Temperament and Character Inventory (TCI), a 240 item self-report questionnaire. As described by Verweij et al., (2010):
Novelty Seeking reflects the tendency to respond strongly to novelty and cues for reward as well as relief from punishment, and is thought to play a role in the activation or initiation of behaviours. Harm Avoidance reflects the tendency to respond strongly to aversive stimuli, which leads to learned inhibition of behaviour, and is thought to play a role in the inhibition or ceasing of behaviours. Reward Dependence reflects the tendency to react strongly to rewards and to maintain behaviours previously associated with reward or relief of punishment, and is thought to play a role in the maintenance or continuation of behaviour. Persistence reflects the tendency to persevere despite frustration and fatigue.
The participants completed a short form of Cloninger's (1986) original Tridimensional Personality Questionnaire (TPQ).1 The fourth dimension of temperament -- Persistence -- was constructed using a small subset of the Reward Dependence questions. The 1986 version of Cloninger's biosocial theory of personality associated Novelty Seeking with low dopamine activity, Harm Avoidance with high serotonin activity, and Reward Dependence with low noradrenaline activity. These were thought to be independent and heritable aspects of personality that influence responses to reward, punishment, and novelty. The TPQ was later revised to include Persistence and also three character dimensions (Self-Directedness, Cooperativeness, and Self-Transcendence) to form the basis of the TCI (Cloninger et al., 1993).

Cloninger's theory of personality is not without its critics. In 2008, Farmer and Goldberg challenged the psychometric validity of the TCI in a target article and in a wonderfully titled reply to Cloninger. A trenchant quote from the latter (Farmer & Goldberg, 2008) is below:
Overall, several core theoretical assumptions and predictions associated with the psychobiological model and TCI-R assessment are either non-falsifiable, in conflict with each other, or not supported by empirical evidence.
So the question arises, are we dealing with a flawed set of personality constructs to begin with? No matter. The scales are widely used, so we'll go on.

For genotyping, single nucleotide polymorphisms (SNPs) across the entire genome were tested for association with each of the four traits. The Illumina and Affymetrix platforms were used. [Those technical and statistical methods are beyond the scope of this blog, so I will leave it to someone else to describe and critique the genotyping aspects of the paper.] Stated succinctly, the results showed that:
No SNPs reached genome wide significance (╬▒ = 7.2*10-8) and the SNP with the lowest p-value for each personality scale explains less than 0.5% of the total variance.
None of the previously identified candidate genes (e.g., serotonin receptor gene, D4 receptor gene) were close to showing a significant relationship with any trait, nor were any of the SNPs with the lowest p value for each trait "in or close to a gene of known relevant function." The authors conclude that "common genetic variants do not contribute substantively to variation in personality." How can this be the case, when 30-60% of the variance in personality should be explained by genetics?
This raises the question of "missing heritability"... Missing heritability has been observed to a large extent in almost all complex traits. Proposed explanations focus on: many variants of very small effect that are yet to be found; rare variants that are poorly detected by available genotyping arrays that focus on variants present in at least 5% of the population; structural variants poorly captured by existing arrays, such as copy number variations; and low power to detect epistasis (interaction between genes). Newer technologies (e.g. whole genome sequencing) and novel statistical approaches combined with larger samples and meta-analyses will contribute to our understanding of the genetic architecture of complex traits.

So don't rush out and spend $1,397 on the Inborn Talent Genetic Test just yet...


Footnote

1 Note that the participants did not complete the full TCI. Did that make a difference? Perhaps not, since two previous GWAS failed to find anything for Eysenck's Neuroticism scale or for the Big Five personality traits.

References

Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH. (1996). Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet. 12:81-4.

Cloninger CR. (1986). A unified biosocial theory of personality and its role in the development of anxiety states. Psychiatr Dev. 4:167-226.

Cloninger CR, Svrakic DM, Przybeck TR. (1993). A psychobiological model of temperament and character. Arch Gen Psychiatry 50:975-90.

Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH. (1996). Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet. 12:78-80.

Gelernter J, Kranzler H, Coccaro E, Siever L, New A, Mulgrew CL. (1997). D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects. Am J Hum Genet. 61:1144-52.

Farmer RF, Goldberg LR. (2008). Brain Modules, Personality Layers, Planes of Being, Spiral Structures, and the Equally Implausible Distinction between TCI-R "Temperament" and "Character" Scales: A Reply to Cloninger. Psychol Assess. 20:300-304.

Herbst JH, Zonderman AB, McCrae RR, Costa PT Jr. (2000). Do the dimensions of the temperament and character inventory map a simple genetic architecture? Evidence from molecular genetics and factor analysis. Am J Psychiatry 157:1285-90.

Holden C (2008). Parsing the genetics of behavior. Science 322:892-5.

Paterson AD, Sunohara GA, Kennedy JL. (1999). Dopamine D4 receptor gene: novelty or nonsense? Neuropsychopharmacology 21:3-16.

Strobel A, Lesch KP, Hohenberger K, Jatzke S, Gutzeit HO, Anacker K, Brocke B. (2002). No association between dopamine D4 receptor gene exon III and -521C/T polymorphism and novelty seeking. Mol Psychiatry 7:537-8.

Verweij, K., Zietsch, B., Medland, S., Gordon, S., Benyamin, B., Nyholt, D., McEvoy, B., Sullivan, P., Heath, A., Madden, P., et al. (2010). A genome-wide association study of Cloninger's Temperament scales: Implications for the evolutionary genetics of personality. Biological Psychology DOI: 10.1016/j.biopsycho.2010.07.018



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