Vad är egentligen problemet?

Transkript

1 Vad är egentligen problemet? Non-shared environment Gene-environment Heritability-miljö interaction Gene-environment environment interaction Epi-genetic effects Andel av variationen Livshändelser 100% 80% 60% 40% 20% 0% Genetik Gemensam miljö Unik miljö "Okontrollerbara" Kontrollerbara Vi påverkar vår egen miljö Ju mer påverkbar miljön är desto högre ärftlighet Plomin, Lichtenstein, Pedersen, McClearn & Nesselroade, 1990, Psychol Aging 1

2 2000 lung cancer cases and 2000 controls 300k SNPs Identified a locus in chromosome region 15q25 Replication: Five lung cancer studies 2,513 lung cancer cases and 4,752 controls Rossouw, JAMA,

3 Crude Crude Adjusted for quantity smoked Lung cancer 1.27 ( ) Lung cancer 1.27 ( ) 1.05 Peripheral arterial disease 1.18 ( ) Peripheral arterial disease 1.18 ( ) 1.04 Genetic influence on environmental variables is the rule not exception Smoking Alcohol Physical activity Dietary habits Personality Life events Marital life Parenting etc Genetic influence on environmental variables is the rule not exception Smoking Alcohol Physical activity Dietary habits Personality (self selection) Life events Marital life Parenting etc 3

4 Conclusion Nonshared environment Genetic and familial effects need to be taken into consideration in epidemiological and psychological studies When RCT is not possible use genetically informative (family data) to understand mechanism ADHD + birth weight discordant pairs (13-14 years) <400 g or 15% difference Birth weight discordant pairs: Paired t-test <400 g or 15% difference (g) Birth weight Odds ratio 9.0 ( ) ADHD score Hultman et al., 2007, J Am Acad Child Adolesc Psychiatry N % increase in ADHDscore* p 8-9 years The twin All with the 204 lower birth weights 13 have 12%.006 more ADHD symptoms years All * % higher ADHD-score for the lighter twin compared to the heavier twin Hultman et al., 2007, J Am Acad Child Adolesc Psychiatry 4

5 Birth weight discordant pairs: Paired t-test <400 g or 15% difference N % increase in ADHDscore* p 8-9 years The twin All with the 204 lower birth weights 13 have 12%.006 more ADHD symptoms MZ Same differences within MZ-twin pairs.05 Association DZ not 98 confounded by 13 genetic or shared years environmental effects All MZ DZ Nonshared environment slutsats Miljö huvudsakligen nonshared Familjemiljön har överraskande (?) liten effekt men kan vara nonshared Skillnad mellan enäggstvillingar måste vara nonshared Systematiska skillnader i nonshared effekter (födelsevikt) kan orsaka skillnader i outcomes (ADHD) * % higher ADHD-score for the lighter twin compared to the heavier twin Hultman et al., 2007, J Am Acad Child Adolesc Psychiatry Gene-environment Twin similarity Parental criticism: Girls 16 year old Correlation 1 0,8 0,6 0,4 0,2 0 Monozygotic Parental criticism Dizygotic - I find faults with her - It is hard for us to get along - She makes me irritated Narusyte, Andershed, Neiderhiser & Lichtenstein, 2007, Europ Child & Adol Psychiatry 5

6 Vad är gen-miljö korrelation? Vad är gener? Vad är miljö? So what? Om miljön beror på gener.... Vad ska vi då tro om sambandet mellan miljö och utfall (psykopatologi) Hur ska man förstå genetiska effekter på miljö? Gen-miljö korrelation (Genotype environment ) 1) Passiv Föräldrar ger en viss miljö (ex böcker) och samtidigt gener (ex intresse för böcker) till sina barn 2) Evokativ Individer beter sig så att de skapar en viss reaktion hos andra (stökiga barn kommer att få föräldrar som vill ha mer kontroll) 3) Aktiv Individer söker sig till miljöer som är i samklang med deras genetiska predisposition (personer med empati söker terapiutbildning) How should we understand genetic influences on environment? Genotype environment Causal effects or confounding? Passive gene-environment Smoking during pregnancy and violent criminality? Confounding - Indirect effects - Passive gen-environment Parents provide a certain environment (ex books) and also transmit genes (ex interest in books) to their children 6

7 Risk for Violent Offense (Population) Risk for Violent Offense (Siblings) 3 3 2,5 2,5 2 2 Risk 1,5 Risk 1, ,5 0, , , , , , , , , , , , ,5 21 Age Age No SDP SDP No SDP SDP D Onofrio et al, 2010, Arch Gen Psychiatry D Onofrio et al, 2010, Arch Gen Psychiatry Causal effects or confounding? Passive gene-environment SDP and academic achievement? Smoking during pregnancy and cognitive function? Yes smoking during pregnancy is associated with child school grade D'Onofrio et al., 2010, Child Development 7

8 SDP and academic achievement? Yes smoking during pregnancy is associated with child school grade No causal effect SDP and academic achievement? Yes smoking during pregnancy is associated with child school grade Probably genetic confounding D'Onofrio et al., 2010, Child Development D'Onofrio et al., 2010, Child Development Causal effects or confounding? Passive gene-environment Smoking during pregnancy and cognitive function? No causal effect! Probably genetic confounding passive gene-environment How should we understand genetic influences on environment? Genotype environment Confounding - Indirect effects - Passive gen-environment Parents provide a certain environment (ex books) and also transmit genes (ex interest in books) to their children Mediation - Direct effects Evocative Individuals act and create a reaction by others (gifted children will get teachers who are more engaged. More engaged teacher cause school performance) Active Individuals seek environments that fits their genetic predisposition (deviant children will hang out with deviant friends. Hanging out with deviant friends increase risk for criminality) 8

9 Percentage of Variance Parental criticism: Girls 16 year old Antisocial behavior Parental criticism as explanation Genetic Shared environmental Nonshared environmental 100% 80% Evocative gene-environment 60% 40% 20% 0% Parental critisism ntisocial Correlation with an behavior 0,4 0,2 0 Parental criticism Association between parenting and antisocial behavior What are the causes? Narusyte, Andershed, Neiderhiser & Lichtenstein, 2007, Europ Child & Adol Psychiatry Narusyte, Andershed, Neiderhiser & Lichtenstein, 2007, Europ Child & Adol Psychiatry Antisocial behavior Parental criticism as explanation Antisocial behavior Parental criticism as explanation Genetic Shared environmental Nonshared environmental Explained by aggression (13 years) "Other" 0,4 0,4 Correlation w ith antisocial beha avior 0,2 0 Parental criticism Evocative gene-environment Child s genes important for the association Can this be due to child s personality? Correlation w ith antisocial beha avior 0,2 0 Parental criticism Evocative gene-environment Child s genes important for the association Children s heritable temperament evoke reactions Starts negative cycles of interaction? Narusyte, Andershed, Neiderhiser & Lichtenstein, 2007, Europ Child & Adol Psychiatry Narusyte, Andershed, Neiderhiser & Lichtenstein, 2007, Europ Child & Adol Psychiatry 9

10 Antisocial behavior Parental criticism as explanation Sambandet mellan parenting och problem hos barn Är det evocative g-e corr? Parental criticism - Genetiska effekter viktiga för parenting Genes (child) Aggressive behavior (childhood) Antisocial behavior (adolescence ) Narusyte, Andershed, Neiderhiser & Lichtenstein, 2007, Europ Child & Adol Psychiatry Narusyte et al., 2008, Developmental Psychology Sambandet mellan parenting och problem hos barn Är det evocative g-e corr? Sambandet mellan parenting och problem hos barn Är det evocative g-e corr? - Genetiska effekter viktiga för parenting - Genetiska effekter viktiga för barnets internaliserande problem - Genetiska effekter viktiga för parenting - Genetiska effekter viktiga för barnets internaliserande problem - Passiv gene-environment Samma gener påverkar parental overinvolvment och internaliserande problem Narusyte et al., 2008, Developmental Psychology Narusyte et al., 2008, Developmental Psychology 10

11 Sambandet mellan parenting och problem hos barn Är det evocative g-e corr? - Genetiska effekter viktiga för parenting - Genetiska effekter viktiga för barnets internaliserande problem - Passiv gene-environment Samma gener påverkar parental overinvolvment och internaliserande problem - Evokativ gene-environment Children s heritable temperament evoke reactions Narusyte et al., 2008, Developmental Psychology Sambandet mellan parenting och problem hos barn Är det evocative g-e corr? - Genetiska effekter viktiga för parenting - Genetiska effekter viktiga för barnets internaliserande problem - Passiv gene-environment Samma gener påverkar parental overinvolvment och internaliserande problem - Evokativ gene-environment Children s heritable temperament evoke reactions - Ingen kausal effekt Narusyte et al., 2008, Developmental Psychology Gene environment slutsats Heritabilitet-miljö interaktion Vi (delvis) skapar våra egna miljöer Passive Evocative Active Samband mellan miljö och utfall kan beror på både arv och miljö. Var försiktigt med kausalitet 11

12 Andel av variationen Utbildningsnivå i födelsekohorter 100% 80% 60% 40% 20% 0% Genetik Gemensam miljö Unik miljö * * Män ** *Lichtenstein, Pedersen & McClearn, 1992, Acta Sociologica **Fischbein, Lange & Lichtenstein, 1997, Scandinavian Journal of Educational Research Andel av variationen Utbildningsnivå i födelsekohorter 100% 80% 60% 40% 20% 0% Genetik Gemensam miljö Unik miljö * * Män ** Kvinnor? *Lichtenstein, Pedersen & McClearn, 1992, Acta Sociologica **Fischbein, Lange & Lichtenstein, 1997, Scandinavian Journal of Educational Research Andel av variationen Utbildningsnivå i födelsekohorter 100% 80% 60% 40% 20% 0% Genetik Gemensam miljö Unik miljö * * Män ** * * Kvinnor ** *Lichtenstein, Pedersen & McClearn, 1992, Acta Sociologica **Fischbein, Lange & Lichtenstein, 1997, Scandinavian Journal of Educational Research Percentage of variance Antisocial behavior: Meta analyses of 51 twin and adoption studies Genetic Shared environment Nonshared environment 100% 80% 60% 40% 20% 0% Antisocial behavior - Violent, aggressive behavior - Crime against property, nonaggressive behavior - Drug related crimes Rhee & Waldman, 2002, Psychol Bull 12

13 Percentage of variance Self-reported delinquency: Boys 16 year old Genetic Shared environmental Nonshared environmental 100% - High ethnic diversity 80% Shared - Low environment educational level more important in disadvantaged areas 60% - High unemployment level 40% - Low buying Heritability power higher in advantaged areas - High crime rate 20% 0% Advantaged Disadvantaged neighbourhoods neighbourhoods Gene-heritability interaction slutsats Ärftligheten beror till en del på vilken miljö man befinner sig i Miljön har betydelse för uttrycket av genetiska skillnader Tuvblad, Grann & Lichtenstein, 2006, Journal of Child Psychology and Psychiatry Gene-environment interaction Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Science. Vol 262.October

14 MAOA mutation and antisocial behavior But. Large family with 5 affected men Borderline mental retardation Abnormal behavior impulsive aggression arson attempted rape exhibitionism Deficiency of enzymatic activity of monoamine oxidase A (MAOA) In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene. No other families with such mutation (yet) found Brunner et al, 1993, Science Is there a gene for criminality? New hope: gene environment interaction? NO Genes affect disposition for emotions and thought processes - increase probability for an (antisocial) behavior Specific environment Individuals behavior pattern Social position Criminality is a social not biological concept 14

15 MAOA and maltreatment Caspi et al, 2002, Science MAOA and maltreatment Slutsatser Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems These findings may partly explain why not all victims of maltreatment grow up to victimize others Results provide epidemiological evidence that genotypes can moderate children s sensitivity to environmental insults Caspi et al, 2002, Science Caspi, et al, 2002, Science 15

16 More gene-environment interaction Questions about gene-environment interaction Is it likely to find interaction effects without main effects? Simulations yielded large numbers of significant models with significant main effect of the environment, no significant main effect of genotype, and significant GxE interaction (Eaves 2006) Gene-environment interaction slutsats Epi-genetiska effekter Specifika gener kan ha betydelse för känsligheten för riskfaktorer i miljön Vissa miljöer kan ha betydelse för uttrycket av genetiska skillnader Hur stor del av variationen förklaras? 16

17 What is next... epigenetics Maternal behavior and epigenetic effects Genetics how organisms can inherit traits by inheriting genes from their parent(s), which encode information for cell function as sequences of DNA Epigenetics biological inheritance that do not directly relate to the inheritance of collections of genes (DNA). heritable changes in gene regulation that occur without a change in DNA sequence (genotype). Mothers differed in pup licking => differences in DNA methylation in offspring (=epigenetic effect) DNA methylation emerged over the first week of life were reversed with cross-fostering persisted into adulthood An epigenetic change in a gene can be established through behavioral programming (=parenting) and can be reversed Weaver et al, 2004, Nat Neurosci Epi-genetiska effekter slutsats Miljön har betydelse för uttrycket av genetiska skillnader Hur stor del av variationen förklaras (hos människor)? Is it likely that there are epigenetic effects without genetic effects? Samspelet mellan arv och miljö Arv och miljö samspelar i utvecklingen beteende och psykopatologi Nonshared environment Gene-environment Gene environment Heritability-environment interaction Gene-environment interaction Epi-genetic effects 17