1. Why are social factors important in genetics (and vice-versa)? Andrew Pickles University of Manchester Methodological challenges for the Twenty-First Century RMP Meeting 22-23 Nov 2007

2. Rapid Change Wholesale change of material since spoke to this topic some 3-4 years ago Previously material still relevant –concerned to contrast environmental variation in population means from variations in within population individual differences where estimates of additive genetic variance dominate and wider shared social factors often apparently negligible. –How heritabilities need careful interpretation and can be entirely environmentally contingent –Nature versus nurture contrast as unhelpful

3. Genetics versus environment: false dichotomy DNA is very distal to the outcomes of interest - there are many intermediate stages at which the environment and the social will modulate genetic effects and vice-versa. There are fewer genes than expected (e.g. too few for even blue-print of just the brain). Normal development requires environmental input. The process of gene expression is proving to be much more complicated than expected.

4. What is the effect of a gene? Depends on who you are (other genes and proximal social factors) Depends on where you are (social context) Depends on your developmental stage Depends on what has happened to you

5. Gene-environment interaction Environmentally contingent expression Dunedin Cohort Study (Caspi, Moffitt et al)

6. MAOA, maltreatment and antisocial behaviour

7. ANTISOCIAL BEHAVIOR AS A FUNCTION OF MAOA ACTIVITY AND A CHILDHOOD HISTORY OF MALTREATMENT (from Caspi et al., 2002) Childhood maltreatment Composite index of antisocial behavior (z scores)

8. Serotonin transporter gene, life events and depression

9. Probability of major depression episode Number of stressful life events EFFECT OF LIFE STRESS ON DEPRESSION MODERATED BY 5-HTT GENE (from Caspi et al., 2003) s/s s/l l/l s/s = short allele homozygous l/l = long allele homozygous s/l = heterozygous

10. COMT, cannabis and schizophrenia

11. SCHIZOPHRENIA SPECTRUM DISORDER: CANNABIS USE INTERACTS WITH GENOTYPE (Caspi et al., 2005) % schizophreniform disorder Met/Met Met/Val Val/Val COMT genotype

12. Learning provides a mechanism for persisting effects Biological systems can learn although this is often referred to as programming

13. Example Systems Immunological response is largely programmed through exposure in early life High risk genotypes (over responding) may benefit from early social exposure to risk agent Neglect can be protective for asthma Day-care can be protective for juvenile onset leukemia What are the kinds of detailed mechanics that could give rise to these effects? A proof of concept

14. Stress, Cortisol and the HPA system

16. Genotypes can confer advantage or disadvantage depending upon the environment. How could disadvantage be moderated? Anxiety is disadvantageous when the environment is benign Q: How does a mother rat teach a pup with a gene that predisposes for anxiety to be less anxious? A: She stops the gene from being expressed.

17. How does she do that? By licking the pup a lot!

18. Licking and stress response The pups with the gene predsiposing for a more anxious response but who are licked more are less fearful, they produce less stress hormones when provoked and their heart rate doesn't go up as much. The licking had to have occurred in the first six days of life. This is now known to be an example of epigenetics

19. Epigenetics DNA does not just hang about in the cell with each bit ready for haphazard transcription and protein production. The DNA strands are organised Histones and methylation

22. Maternal behaviour, methylation and pup behaviour Some rat pups inherit a gene variant for cortisol that can make them anxious. At birth it is unmethylated. If the rat pup is licked a lot in the first six days, a single methyl group (CH3) becomes attached at one specific location on the DNA in brain cells. This makes it impossible for the gene to be transcribed. The gene is silenced by the mother rats behaviour and the rat pup is placid. Remove the methyl group (can be done chemically) and the rat pup reverts to being anxious, consistent with its genotype.

23. Many concepts, skills and fields of research Careful description of social behaviour and social development Inter-generational cultural transmission (in fact occurs beyond parent child to grand-parent child because some aspects of methylation can be heritable) Developmental biology Detailed organ specific gene-expression, cell biology, experimental design (cross-fostering), pathology etc

24. Genetics and inference for causal environmental effects Discordant twins Mendelian randomisation

25. MZ (Identical) co-twin controls In longitudinal studies we might control for omitted variables by examining how change in outcome (difference between time 1 and time 2) is associated with change in environmental exposure MZ differences in outcome can be similarly compared with differences in exposure

26. Path Diagram Instrumental Variable Model Note: Errors E2 and E3 are correlated (unmeasured confounder) V1 has no direct effect on V3. This is the exclusion restriction

27. Finding plausible IVs is the problem Can we find genes that might meet the exclusion restriction Does alcohol causally increase risk of depression or do depressed people self-medicate with alcohol? There is a genotype that gives deficient alcholol dehydrogenase. Individuals with this genotype (10% UK, 50% in Japan) enjoy alcohol less and drink less. Using this genotype as an instrument ( Mendelian randomisation ) suggests alcohol increases risk of depression.

28. Conclusions For social and many health outcomes effects of genes are socially mediated and moderated Time-restricted social inputs can have time- persistent effects through programming. Epigenetics provides one such mechanism. Genetic designs provide another tool for unravelling social processes We need social science informed genetics and genetically informed social science.