Genes or Jeans: Some Reflections on the Strengths & Limits of Genetic Research

1. Genes or Jeans:Some Reflections on the Strengths & Limits of Genetic Research Michael Levine, Ph.D. – Kenyon College With Considerable Support from Carolyn Costin, M.A., M.Ed. – Monte Nido & Linda Smolak, Ph.D., Kenyon College

2. Contentions and Controversies “Genetic research has revolutionized our understanding of eating disorders” (Description of Dr. Cynthia Bulik’s forthcoming talk at the Renfrew Conference) “Certainly, cultural attitudes towards standards of physical attractiveness have relevance to the psychopathology of eating disorders,but it is unlikely that cultural influences in pathogenesis are very prominent” (Kaye & Strober, 1999, p. 891; emphasis added) “Research on the etiology of eating disorders has lagged behindother areas of psychiatry, in part due to the imminent plausibility of sociocultural theories about the illness. . . The face validity of these explanations has inhibited our progress due to a burden of plausibility. The sheer convenient believability of sociocultural explanations has influenced research directions and hindered recognition of the seriousness of eating disorders” (Bulik, 2004, p. 165; emphasis added)

3. Establishing a Risk Factor: Admissable “Scientific Evidence” • Cross-sectional, correlational (e.g., from case control studies) – current and retrospective • Prospective, longitudinal data with statistical controls • Experimental data --- laboratory, treatment-oriented, prevention-oriented • Meta-analyses • Other statistical summaries and analyses

4. The Sociocultural Perspective: A Researh-Based Approach Sociocultural variables are causalfactors in the development of variable (causal?) risk factors (Jacobi, 2005; Jacobi et al., 2004; Stice, 2002) for eating problems and eating disorders. • Negative body image • Weight concerns • Thinness and/or • muscularity/leanness • schema Sociocultural Factors or Pressures Continuum of Clinically Significant Disordered Eating Parents Parents Peers • Negative affect • “Negative self-concept” Media

5. MOREOVER: A Sociocultural Model Can Account for • The MassiveGender Difference • The Secular Trends – we can’t ignore population-based increases in antisocial behavior, drug use/abuse, depression, eating disorders, and obesity • Cross-Cultural Differences in Prevalence, Incidence, and Expressions • Migration Data

6. What About the Rarity of ED’s?A Look at Risk Factors & Probability (Hanson, 2004) If there were 4 (relatively) independent risk factors for bulimia nervosa, then to achieve a population frequency of .02 (the point prevalence), each would have to occur at a frequency of .38 in the population, because .38 to the 4th power (.384) = .0208. “The factors that lead to schizophrenia, as Dr. Gottesman taught us, are multiple. These factors must be quite common in the population and thus are not necessarily abnormal. [We need to] get out of our mindset of searching for abnormal schizophrenia genes and broaden our view to look at normal individual genetic variation in conjunction with exposure to common environmental agents” (p. 214)

7. But How Can You Ignore Genetics, OrTheir Links to, e.g., Serotonin or Temperament? • A reasonable, important question -- But let’s think very carefully about what taking genetics into consideration means -- theoretically -- methodologically -- practically • And let’s equalize the burden of proof – • Genes –> neurotransmitter systems –> neurological systems and temperament (or OCPD)  responsiveness to or creation of environments  risk factors  ED • Can’t just present correlations and claim you have the upper hand. . . .

8. The “Heritability” Estimate – Is Not/Is So • NOT a statement, or a proof, that “genes cause the behavior or disorder in question” – correlation, even for twins, does not equal causality • NOTa demonstration that characteristics are fixed, unchangeable, or unresponsive to environmental change Hereditability is: “a statistical indicator that speaks to the confidence that one might have in inferring that genetic differences among individuals account for more than zero of the reliable variance in a trait. . .” -- Rende, 2004, p. 117

9. We Certainly Need to Be Careful and Sensible • Consider the following imaginary example (From Lerner, 2002, p. 253): A long-standing law dictates that only men can hold positions of leadership in a society. 10,000 people are chosen at random from the society. People could be classified into two groups: Those with absolutely no chance at being elected to a position of leadership and those with some meaningful chance. All the difference in eligibility between the two groups can be summarized, i.e., accounted for, by genetic difference. The heritability of eligibility for elected office is thus 100%. Is the difference in eligibility “genetic in nature”? AND Will genes for eligibility eventually be found? AND -- “behavior genetics is concerned with the ‘what is’ rather than the ‘what could be’ or the ‘what should be” – Richard Rende

10. Let’s Be Careful and Not Get Carried Away:Bulik et al. (2006) – Archives of General Psychiatry Type of Twin Lifetime AN Status MZ DZ Neither 1,802 2,375 Discordant 14 33 Concordant 1 1 Pairwise Concordance .07 .03 Proband-wise Concordance .125 .057 Tetrachoric r .56 .36 Lifetime prevalence = .006

11. Let’s Not Get Carried Away:Bulik et al. (2006) – Archives of General Psychiatry Type of Twin Lifetime AN Status MZ DZ Neither 1,802 2,375 Discordant 14 33 Concordant 1 1 Pairwise Concordance .07 .03 Proband-wise Concordance .125 .057 Tetrachoric r .56 .36 estimate of heritability = .56(95% confidence interval = .00 - .87) shared environment= .05 (CI = .00 - .64) unique environment= .38 (CI = .13 - .84).

12. Being Careful and Sensible: Twin Studies and Gene-Environment “Interactions”[See Rutter et al., 2001; Rutter & Silberg, 2002] • Diathesis-Stressor interactions (e.g., certain alleles X life events) are not part of this design and have not yet been investigated • Gene-Environment correlations of the passive and evocative type are subsumed under the genetic effect • This diminishes the impact of environment and the interplay between genetic potential and environment • This contradicts the core assumption of the twin methodology • This does not mean that environments – or the effects of environments - are “determined” and “fixed” by genes (such that we can blame those who are suffering. . . .) – behavior creates and responds to environments, and behavior reflects developmental history, including genotype, experiences, psychological constructions, and “epigenetic interactions” (Turkheimer, 2004) • Differences in, and the relationship between, environmental and genetic mediation cannot be determined without longitudinal [twin] studies that enable comparisons of what predicts what over time

13. Sensible Conclusions: At this Point in Time • It does not make any sense from a theoretical or empirical position to claim that “All instances of disordered eating are genetic” or even that “eating disorders are a genetic illness” • There are no, or precious few, data to support the claim that “eating disorders are caused primarily by genetics” • In polygenic conditions, genes don’t “cause” anything, they contribute to liability – “drive for thinness” and “fear of fat” – let alone sexual abuse and objectification-- are not reducible to a set of genes creating proteins and neurotransmitters. . . . • And in most psychiatric disorders the majority of variation examined in twin studies is attributable to non-genetic effects — and that “shared” as well as environmental effects have been shown to operate in areas of “disorder” related to “socialization” such as drug abuse and criminality • “For most diseases contributing importantly to mortality in Western populations, epidemiologists have long known that non-genetic factors have high attributable risks, often at least 80 or 90% even when the specific etiological factors are not clear” (Willett, 2002, p. 695). • And there is at present evidence that genetic liability may not contribute significantly to individual differences in very important risk factors such as EDE-weight concerns and undue influence of weight and shape on self-concept

14. Sensible Conclusions: • Reinforcing the need for well-articulated models, careful attention to methodology (including outcome variables), and an evidentiary basis • Emphasizing the fact that individual differences in genetic constitution contributes to individual differences in liability for a spectrum of disordered eating – and that some families and thus some individuals are at particularly high risk due to genetic vulnerability • gene-environment interactions and transactions

15. Potential Common Ground • Advancement of the fieldin recognized and “legitimate” ways • Rich understanding of the ways in which genes, proteins, neurotransmitters, neuronal functioning, brain organization, experience, families, subcultures, and so forth interact in both directions – in an epigenetic, reciprocally determined fashion – to influence normal and abnormal development • Preventionor modulationof those variable factors (whether they be “shared” or “unshared” environments) that constitute and/or activate various forms of individual—and sociocultural—vulnerability

16. “Don’t Bring Me Down” “Studying important human behaviors scientifically is vexing. The field of behavior genetics repre-sents an incomplete attempt. Similar limitations apply to psychobiology and to environmentally oriented social science. If everyone were frank about the limitations of their chosen field, we might all be more able to appreciate the valid contributions of others, enabling us to commence work on the prodigious task of formulating a solid scientific basis for the human sciences” (p. 152) Turkheimer, Goldsmith, & Gottesman (1995) => See Wade, Klump, and Bulik (2003)