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Gene Expression, Biological Psychiatry, & the Family

Gene Expression, Biological Psychiatry, & the Family. Douglas A. Kramer, MD, MS University of Wisconsin–Madison. December 8, 2006. Part I: Gene Expression. Ontogeny (classical biology) Gene – environment interaction Gene x Environment interaction (GxE)

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Gene Expression, Biological Psychiatry, & the Family

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  1. Gene Expression, Biological Psychiatry,& the Family • Douglas A. Kramer, MD, MS • University of Wisconsin–Madison December 8, 2006

  2. Part I: Gene Expression • Ontogeny (classical biology) • Gene – environment interaction • Gene x Environment interaction (GxE) • Nature – nurture interplay (Rutter) • Gene – environment interplay (Rutter)

  3. Popular Press • “The aim is to determine how genes, environment and their interplay fit into the mix that gives rise to autism and other neurodevelopmental disorders.” • CDC policy regarding environmental factors in the etiology of autism. Lidia Wasowicz, UPI Senior Science Writer, November 17, 2006.

  4. “Genetics” • “science of heredity and variation” • Greek: origin, source • DNA not required • epigenetics • culture and memes • speciation Lincoln & Boxshall, 1987.

  5. “A word of advice, Durk. It’s the Mesolithic. We’ve domesticated the dog, we’re using stone tools, and no one’s naked anymore.” Gary Larson, 1993.

  6. Gene Expression Steps • Genome (DNA) • transcription • Messenger RNA (mRNA) • translation (protein synthesis) • Protein (amino acid chain) Tamarin, 1999.

  7. 1. Golden Hamster Aggression(social experience & traits) • Male golden hamsters exposed during adolescence to aggressive adults. • As adults, they were more likely to attack younger and weaker intruders. • 50% reduction in vasopressin staining in anterior hypothalamus. • Social experience + normal genome  permanent changes in brain chemistry = gene expression. Delville et al., 1996

  8. 2a. Species Differences(aggression in mice) • Peromyscus californicus: male territorial aggression, long-term pair bonds (monogamous), & male parental care. • Peromyscus leucopus: less aggressive, polygynous mating system, & lack male parental care. • greater attack latencies (p < .003) Bester-Meredith et al., 1999

  9. 2b. Cross Fostering Behavior Bester-Meredith & Marler, 2001

  10. Control white-footed mice Control California mice Cross-fostered white-footed Cross-fostered California mice Bester-Meredith & Marler, 2001 2b. Bed nucleus of the stria terminalis

  11. GxE: Trait CharacteristicDecreased Aggression • only possible explanations are decreased: • TRANSCRIPTION of vasopressin mRNA • TRANSLATION of vasopressin polypeptide

  12. 3. Rat Behavior & Physiology(immediate experience & mRNA) • mRNA for the prolactin receptor (PRL-R) • elevated late in gestation • remains elevated during lactation • production of PRL-R mRNA ceases if pups removed from lactating female • resumes if pups returned Sugiyama et al., 1996

  13. GxE: State CharacteristicMaternal Behavior • immediate experience  • transcription  • mRNA  • translation  • protein synthesis  • maternal behavior

  14. “Did you or did you not tell him I was a Homo sapiens?” Jim Unger, 2004

  15. 4. Study Design: Wahlberg, 1997 • Finnish Adoptive Study of Schizophrenia • all women hospitalized in Finnish psychiatric hospitals between 1960 – 1980 • 19,447 women • exclusions: OBS, severe MR, alcoholism • adopted-away offspring of schizophrenic and schizophrenic-spectrum mothers • exclusions include adoptions by relatives, and adoptions after age 4 years Wahlberg, Wynne et al., 1997

  16. 4. High Genetic Risk Group • 167 biological mothers hospitalized for schizophrenia or a paranoid psychosis • 183 adoptees considered at HIGH genetic risk Wahlberg, Wynne et al., 1997

  17. 4. Low Genetic Risk Group • 204 adoptees considered at LOW genetic risk • 202 biological mothers • no psychiatric diagnosis, or non-schizophrenic spectrum diagnosis • matched for adoptee age, adoptee parent ages, gender, age at placement, SES, urban/rural residence, one/two rearing parents Wahlberg, Wynne et al., 1997

  18. 4. Disordered Thinking • Rorschach analysis by psychologists blind to biological risk & subject research category • high & low risk adoptees • both adoptive & biological parents • Index of Primitive Thought (Friedman, 1952) • developmentally lowest functioning • contamination, confabulation, & fabulized combination Wahlberg, Wynne et al., 1997

  19. 4. Communication Deviance (CD) • CD is a language production that is ambiguous and hard for listener to follow • Analysis of parent language production on Rorschach responses in 42 categories • Communication Deviance Scoring • measure of understandability of discourse • assessment of the impact on the listener • instances of CD/Rorschach - add parents Wahlberg, Wynne et al., 2001

  20. 4. Results: Wahlberg et al. (1997) • No increased risk for disordered thinking • adoptees at HIGH genetic risk in low CD environment • adoptees at LOW genetic risk in high CD environment • GxE = neither G alone, nor E alone, was sufficient to produce a disordered thinking phenotype in adoptees Wahlberg, Wynne et al., 1997

  21. 4. Wahlberg, Wynne, et al., 1997 (continued) • Significant risk for disordered thinking (p = .01) • adoptees at HIGH genetic risk • in an environment with HIGH CD • GxE = combination of high G and disordered E (parental CD) results in an increased risk for disordered thinking in adoptees • only the third condition (GxE) matters Wahlberg, Wynne et al., 1997

  22. 4. Disordered Thinking vs. Communication Deviance Protective & predisposing Wahlberg, Wynne et al., 1997

  23. 5. Tienari, Wynne et al., 2004 (2nd analysis) • 190 adoptees considered at HIGH genetic risk from 174 biological mothers • 137 adoptees from 125 mothers dx with schizophrenia • 53 adoptees from 49 mothers dx with schizophrenia-spectrum disorder • 192 adoptees considered at LOW genetic risk from 190 biological mothers • Median age at 2nd assessment = 35 years Tienari, Wynne et al., 2004

  24. 5. Family Functioning: 2nd analysis • Oulu Family Rating Scale (OPAS) • Beavers Timberlawn Family Evaluation Scale, Lewis (1976) • 33 subscales - operationally defined • Low OPAS score = relatively healthy family behaviors and relationship patterns • Dysfunctional family patterns • critical/conflictual, constricted, boundary problems Tienari, Wynne et al., 1994

  25. 5. Results: Spectrum Disorders2nd analysis • LOW genetic risk adoptees dx spectrum disorder ~ 5% irrespective of OPAS score • HIGH genetic risk adoptees dx spectrum disorder • 5.8% in families with low OPAS scores • 36.8% in high OPAS families, (p < .001) Tienari, Wynne et al., 2004

  26. 5. Results: Schizophrenia Dx2nd analysis • Age-corrected morbid risk of developing schizophrenia for a LOW genetic risk adoptee = ZERO • Age-corrected morbid risk of developing schizophrenia for a HIGH genetic risk adoptee • 1.49% in “healthy” family (low OPAS) • 13.04% in “dysfunctional” family (high OPAS) Tienari, Wynne et al., 2004

  27. 6&7. Dunedin Multidisciplinary Study(human studies & known alleles) • 1972 birth cohort of 1037 children in New Zealand • 96% intact at age 26 • study of 442 boys for GxE • polymorphism involving the MAOA gene • maltreatment during ages 3 - 11 • study of 847 individuals for GxE • two alleles involving the serotonin transporter gene • stressful life events from 21 - 26 Caspi et al., 2002, 2003

  28. 6. Maltreatment Study • 37% low activity, 63% high activity MAOA • assumption: low activity MAOA predisposes to overresponding to perceived threats • 8% severe, 28% probable, & 64% no maltreatment between ages 3 - 11 • GxE = the 12% with low MAOA + severe or probable maltreatment (55 boys)  44% of violent convictions by age 26, (p < .001) • GxE = these 55 boys 3x more likely convicted of violent crime by age 26 than 99 boys with high MAOA activity and maltreatment Caspi et al., 2002

  29. 7. Depression Study • short allele (s/) associated with lower transcriptional activity of the serotonin transporter gene (5-HTT) promotor • 17% s/s homozygous, 51% s/l heterozygous, 31% l/l homozygous for polymorphism • GxE = 33% risk of major depression with s/s or s/l if ≥ 4 stressful life events from ages 21-26 vs. 17% for l/l polymorphism group, (p = .02) • GxE = s-allele + ≥ 4 stressful life events = 10% of sample, & accounted for 23% of major depression Caspi et al., 2003

  30. “I need some books about this wide.” Jim Unger, 2005

  31. 8. Pelvic Spine, G. aculeatus ventral view - bony = red 3-spine sticklebacks Shapiro et al., Nature, 428, 2004

  32. 8. Pitx1 Expression(gene expression & speciation) • Paxson benthic stickleback fish • freshwater version of marine three-spine stickleback • large spine in pelvic fin absent in freshwater version • evolved in < 10,000 generations • natural selection = lower concentrations of calcium ions, or predation by invertebrates Shapiro et al., Nature, 428, 2004

  33. 8. Source of Phenotypic Change • Not DNA mutations • Pitx1 gene not expressed in pelvic region of Paxson benthic stickleback • Pitx1 gene intact and unchanged and is expressed in 4 other regions of the freshwater version • When & where Pitx1 gene expressed determines the ultimate phenotype Shapiro et al., Nature, 428, 2004

  34. 9. Epigenetics & Conceptual Space • Epigenetics is the study of . . . • stable alterations in gene expression . . . • by non-genetic mechanisms . . . • resulting in stable alterations in phenotype. • Operates in the conceptual space between the genome and the environment.

  35. 9. Epigenesis History • Webster = “development involving gradual diversification and differentiation of an initially undifferentiated entity (as a spore) - Aristotle.” • Piaget = “preformation,” i.e., with a Homunculus, an entirely preformed miniature human being • Cambridge Natural History = “the interaction of genetic factors and developmental processes, through which the genotype is expressed in the phenotype.” • Prefix “epi-” = “on, at, besides, after, over”  epigenetics = on or over the genes

  36. 9. Epigenetic Programming 1(cytosine methylation & histone acetylation) • maternal behavior in rats toward their offspring either high or low in: • pup licking and grooming (LG) • arched-back nursing (ABN) • offspring of high LG-ABN mothers are: • less fearful as adults • less responsive to stress on HPA axis Weaver et al., 2004

  37. 9. Epigenetic Programming 2 • cross-fostering produced rats with the stress-response patterns associated with their rearing mother (p < .05) • within 12 hours of birth • decreased glucocorticoid receptor (GR) mRNA in the offspring of high LG-ABN mothers raised by low LG-ABN mothers • gene expression altered at the level of transcription of messenger RNA Weaver et al., 2004

  38. 9. DNA Methylation • Stable variations in gene expression • associated with chromatin structure changes • involving DNA methylation • C-methylation in the GR promotor sequence • lower for offspring of high LG-ABN mothers • reversed by cross-fostering Weaver et al., 2004

  39. 9. Results of low & high maternal LG-ABN Weaver et al., 2004

  40. 10. Epigenetic Differences in Twins(human epigenetics) • Monozygous twins share a common genotype • Significant phenotypic discordance observed • Studied DNA methylation & histone acetylation • MZ twins epigenetically indistinguishable early • Older MZ remarkably epigenetically different • Leading to differences in gene expression portrait Fraga et al., 2005

  41. Part II: Biological Psychiatry • Biology, 5th ed., Campbell, Reece, & Mitchell, has 55 chapters. • John Bowlby, “biological psychiatry stolen by the physiological psychiatrists.” • Species-specific behavior patterns (Ethology).

  42. Biological Units & Levels of Selection • species • population • community • kinship group • family • individual • gene Wilson, DS, and Sober, E. 1994. Reintroducing group selection to the human behavioral sciences. Behavioral & Brain Sciences, 17:585-654.

  43. Shih Tzu with a Chemical Imbalance Get Fuzzy, by Darby Conley, 2003.

  44. Evolutionary Tree

  45. Bonobo (Pygmy Chimpanzee)

  46. Orangutan Photo

  47. Adult Homo sapiens

  48. Primate Family Structure

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