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with the work by Raison et al9 in a similar sample, showing that patients who developed a greater increase in depressive symptoms during pegIFN-a2b and ribavirin treatment were less likely to show virologic response at the end of the treatment. As Raison et al9 suggest, a persisting or less responsive virus could cause worse fatigue and depression by inducing inflammation and immune activation. However, it is also possible that the worse fatigue or depression and the lack of response are both associated with a third factor, for example, MHC class II genotypes regulating the immune response. Finally, patients who experience worse fatigue and depression could be less compliant with therapy, and future studies should measure plasma concentrations of the antiviral agents to clarify this point. It is of note that Loftis et al10 described results that are apparently in contrast with our work and the work by Raison et al.9 In fact, they found that depression is associated with increased virologic response to (nonpegylated) IFN-a and ribavarin treatment.10 An important difference in the study by Loftis et al10 is that all patients who reached a threshold for depression were started on antidepressant treatment; in our study, and in the study by Raison et al,9 the antidepressant treatment was dictated by clinical judgment of patient’s distress. This ‘assertive’ approach explains the high rate of patients receiving antidepressants in the study by Loftis et al: 13 out of 39 subjects (33%),10 vs three out of 29 (10%) in our study, and five out of 60 (8%) in our previous study on a different sample using similar clinical guidelines.1–3 It is possible that the antidepressant treatment—rather that the depression—explains the better virologic response rate, as the antidepressant treatment may allow better compliance and prevent reductions in the doses of IFN-a and ribavarin. We believe that clarifying the mechanisms by which IFN-a induces psychopathological symptoms will help understanding not only the predictors of the psychiatric outcome but also the predictors of the therapeutic outcome. C Maddock1, S Landau2, K Barry3, P Maulayah3, M Hotopf2, AJ Cleare2, S Norris3 and CM Pariante2 1 Maudsley Hospital, London, UK; 2Institute of Psychiatry, King’s College London, London, UK; 3Institute of Liver Studies, King’s College London, London, UK Correspondence should be addressed to Dr CM Pariante, MD, MRCPsych, PhD, Division of Psychological Medicine, PO51, Institute of Psychiatry, King’s College London, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK. E-mail: [email protected]

1 2 3 4

Pariante CM et al. Lancet 1999; 354: 131–132. Pariante CM et al. N Engl J Med 2002; 347: 148–149. Maddock C et al. J Psychopharmacol 2004; 18: 41–46. Beck AT et al. Arch Gen Psychiatry 1961; 4: 561–571.

5 Spielberger CD et al. Manual for the State-Trait Anxiety Inventory (Self-Evaluation Questionnaire). Consulting Psychologist Press: Palo Alto, CA, 1970. 6 Chalder T et al. J Psychosom Res 1993; 37: 147–153. 7 Stewart AL, Ware Jr JE. Measuring Functioning and Well-Being: The Medical Outcomes Study Approach. Duke University Press: Durham, NC, 1992. 8 Capuron L et al. Neuropsychopharmacology 2002; 26: 643–652. 9 Raison CL et al. Brain Behav Immun 2005; 19: 23–27. 10 Loftis JM et al. Neurosci Lett 2004; 365: 87–91.

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Dopaminergic polymorphisms associated with self-report measures of human altruism: a fresh phenotype for the dopamine D4 receptor Molecular Psychiatry (2005) 10, 333–335. doi:10.1038/sj.mp.4001635 Published online 18 January 2005 SIR—The paradox of human altruism, helping others and thereby reducing one’s own fitness, has confounded evolutionary biologists since the days of Darwin.1 Nevertheless, altruistic behavior is commonplace and a unique feature of human altruism is that it extends beyond Hamilton’s concept of ‘inclusive fitness’, which explains altruistic acts by including helping genetically related individuals, and even beyond reciprocal altruism and reputation-based altruism. However, almost nothing is known regarding specific genes contributing to this behavior despite twin studies2 demonstrating that a significant proportion of the differences between people regarding prosocial attitudes is due to heredity. Towards the goal of identifying specific genes associated with altruism, 354 nonclinical families with multiple siblings were inventoried for scores on the Selflessness Scale.3 This questionnaire measures the propensity to ignore ones own needs and serve the needs of others, or in other words altruism. Subjects were also inventoried on Cloninger’s TPQ4 since the Reward subscale of this questionnaire taps into elements of human altruism such as empathy. We examined two dopaminergic genes in these subjects that we hypothesized might contribute to prosocial or altruistic traits based on the role a single variant of these genes plays in attention deficit hyperactivity disorder (ADHD), often comorbid with antisocial behavior. Meta-analyses5,6 show that the dopamine D4 receptor (DRD4) exon III 7 repeat (D4.7) and the DRD5 148 bp microsatellite variant have both been associated with ADHD in some but not all studies. We reasoned that if one variant contributes to antisocial traits, then conversely the absence of this variant or Molecular Psychiatry

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334

Table 1

Association between DRD4 exon III repeat region, IGF2 ApaI and DRD5 and self-report measures of altruism

Marker

Allele

DF

CHISQ

Multivariate test statistic 3 traits selected: KIN, NON-KIN and NON-CARING Model recessive; test biallelic D4EXON3 4 0.683 203 D4EXON3 7 0.199 49

2 2

14.061 2.140

0.0008 0.3430

Model dominant; test biallelic IGF2APA1 A IGF2APA1 G

0.315 0.684

203 108

2 2

2.332 9.960

0.311 0.006

Model additive; test biallelic DRD5 146 DRD5 148

0.071 0.378

91 306

2 2

9.619 7.210

0.008 0.027

Marker

Afreq

Fam#

S

E(S)

Var(S)

Z

P

Univariate tests DRD4 exon III Model recessive; test biallelic KIN D4EXON3 4 D4EXON3 7

0.683 0.199

203 49

1286.000 190.000

1136.750 194.250

4111.646 826.938

2.328 0.148

0.019 0.882

NON-KIN D4EXON3 D4EXON3

4 7

0.683 0.199

201 48

2406.000 342.000

2049.000 329.750

13416.958 2508.438

3.082 0.245

0.002 0.806

NON-CARING D4EXON3 D4EXON3

4 7

0.683 0.199

203 49

1286.000 190.000

1136.750 164.250

4111.646 826.938

2.328 0.148

0.019 0.882

Allele

Afreq

Fam#

P

Univariate tests IGF2 ApaI Model dominant; test biallelic KIN IGF2APA1 IGF2APA1

A G

0.315 0.684

192 105

1436.000 1078.000

1525.833 945.000

4644.944 1769.250

1.318 3.162

0.187 0.001

NON-KIN IGF2APA1 IGF2APA1

A G

0.315 0.684

197 104

2779.000 2042.000

2912.000 1777.000

14475.750 6583.250

1.105 3.266

0.268 0.001

NON-CARING IGF2APA1 IGF2APA1

A G

0.315 0.684

192 105

1436.000 1078.000

1525.833 945.000

4644.944 1769.250

1.318 3.162

0.187 0.001

Univariate tests DRD5 Model additive; test biallelic KIN DRD5

148

0.378

306

3070.000

3257.833

8404.928

2.049

0.040

NON-KIN DRD5

148

0.378

304

5516.000

5930.167

28275.527

2.463

0.013

NON-CARING DRD5

148

0.378

306

3070.000

3257.833

8404.928

2.049

0.040

We tested for presence of association between various polymorphisms and scores on the questionnaires, using the family-based association test (FBAT) http://www.biostat.harvard.edu/Bfbat/fbat.htm, which allows for inclusion of both triads and extended families in the analysis and is adjusted for population admixture.10 All markers were in Hardy–Weinberg equilibrium (using Merlin). ‘afreq’ is allele frequency. ‘fam#’ is the number of informative families, that is, families with at least one heterozygote parent. S is the test statistic for the observed number of transmitted alleles. E(s) is the expected value of S under the null hypothesis of no association in the presence of linkage. The values for KIN, NON-KIN and NON-CARING were adjusted for sex and age. The original Selflessness questionnaire consists of 15 items. We undertook factor analysis on 1006 subjects. Using Principal Component Analysis (Promax rotation with Kaiser normalization), we found a three component solution (KIN, NON-KIN, NON-CARING) that accounted for B38% of the variance. Reliability analysis gave an alpha Chronbach ¼ 0.63, which compares favorably with the original description of this scale (alpha ¼ 0.61). Genotyping methods and details on the questionnaire are available from the corresponding author on request.

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the presence of other variants might contribute to altruistic behavior. We also genotyped three SNPs7 in the insulin-like growth factor 2 gene (IGF2), an imprinted gene on chromosome 11p15.5 that is an attractive candidate since some studies connect this class of growth factors to survival of dopamine neurons specifically8 and with neural development overall. As shown in Table 1, significant multivariate associations were observed between the Selflessness Scale and the DRD4 exon III (D4.4), the IGF2 Apa I (‘G’) and DRD5 (146 and 148 bp repeat) polymorphisms. Univariate analysis also showed significant associations with the most common D4.4 allele, the IGF2 ApaI (‘G’ allele) and DRD5 (148 bp repeat, negatively associated) for all three factors (KIN, NON-KIN and NON-CARING). We also found a significant association (P ¼ 0.002) between the D4 4/4 genotype and TPQ reward (data not shown). No association was observed between three DRD4 promoter region polymorphisms, including the C521T SNP, nor with any haplotypes (data not shown). Haplotype analysis of the three IGF2 SNPs was slightly more informative than single SNP analysis (data not shown). We conjecture that the balanced maintenance of both the D4.4 and D4.7 repeats in human evolution9 is related to the need for diverse behavioral phenotypes in human populations partially determined by this gene, altruistic and prosocial (D4.4) vs a more aggressive, novelty seeking or perhaps even antisocial type (D4.7). All three genes (DRD4, IGF2 and DRD5) in the current study were associated with both the KIN and NON-KIN subscales. These results suggest the notion that the genetic architecture of altruism in humans is partly built from genes that drive an altruistic behavioral pattern regardless of kin considerations. It would be of interest whether there are KIN/NON-KIN-specific polymorphisms, as well. We also suggest the notion that the linkage between reward and altruistic attitudes provide the neurochemical substrate and ‘hard wiring’ needed to drive acts that benefit others even at the expense of

reducing one’s own fitness. We ‘feel good’ and rewarded by a dopamine pulse when doing good deeds. Selection for specific polymorphisms that ‘reward’ altruistic acts via brain dopaminergic pathways is the grist for the evolutionary mill.

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Acknowledgements This research was partially supported by the Israel Science Foundation founded by the Israel Academy of Sciences and Humanities (RPE). R Bachner-Melman1,2, I Gritsenko3, L Nemanov3, AH Zohar4, C Dina5 and RP Ebstein1,2,3 1 Department of Psychology, Hebrew University, Jerusalem, Israel; 2Scheinfeld Center of Human Genetics for the Social Sciences, Hebrew University, Jerusalem, Israel; 3 S Herzog Memorial Hospital, Jerusalem, Israel; 4Department of Behavioral Sciences, Ruppin Academic Center, Emek Hefer, Israel; 5Ge´ne´tique Maladies Multifactorielles—Institut de Biologie de Lille, UPRES A 8090 Lille, France Correspondence should be addressed to Professor R Ebstein, Department of Psychology, Hebrew University, Mt Scopus, Jerusalem, Israel. E-mail: [email protected]

1 Fehr E, Fischbacher U. Nature 2003; 425: 785–791. 2 Asbury K, Dunn JF, Pike A, Plomin R. Child Dev 2003; 74: 933–943. 3 Bachar E, Latzer Y, Canetti L, Gur E, Berry E, Bonne O. Int J Eating Disord 2001; 31: 43–48. 4 Cloninger CR. Arch Gen Psychiatry 1987; 44: 573–588. 5 Faraone SV, Doyle AE, Mick E, Biederman J. Am J Psychiatry 2001; 158: 1052–1057. 6 Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ et al. Am J Hum Genet 2004; 74: 348–356. 7 Gaunt TR, Cooper JA, Miller GJ, Day IN, O’Dell SD. Hum Mol Genet 2001; 10: 1491–1501. 8 Shavali S, Ren J, Ebadi M. Neurosci Lett 2003; 340: 79–82. 9 Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL et al. Am J Hum Genet 2004; 74: 931–944. 10 Laird NM, Horvath S, Xu X. Genet Epidemiol 2000; 19(Suppl 1): S36–S42.

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