Seventy years since Kanner s account, what do we think causes autism in 2013?

Transcription

1 Seventy years since Kanner s account, what do we think causes autism in 2013? 24 th September 2013 Karolinska Institutet Dr Angelica Ronald Genes Environment Lifespan laboratory, Centre for Brain and Cognitive Development, Birkbeck, University of London

2 70 years ago b.1943 b.1947 b.1943 b.1941

3 1943/1944 Leo Kanner Hans Asperger He often spun the forms around... the whole performance was very repetitious. He never used language as a means of communicating with people.... He did not respond to being called and did not look at his mother when she spoke to him. (Kanner 1943, p 237, describing boy with early infantile autism)

4 ASD Socialcommunication Restricted Repetitive behaviours and interests American Psychiatric Association (2013)

5 Autism Everyone else

6 Outline 4. Clues from Comorbidity 1. An Etiological Continuum 3. The Fractionable Autism Triad 2. Female Risk

7 Risk Factors Genetic Common variants Copy number variants Rare mutations De novo mutations Genetic syndromes Environmental Obstetric complications Prenatal maternal stress

8 Genetic Common variants Copy number variants Rare mutations De novo mutations Genetic syndromes Risk Factors Methylation Environmental Obstetric complications Prenatal maternal stress Parental age

9 The Classic Twin Design Monozygo'c (MZ) twins: share all DNA code Dizygo'c (DZ) twins: share on average 50% of their DNA code Plomin et al., (2008) Behavior Gene-cs, 5th Edi'on

10 Both genes and environment MZ play a role DZ MZ = Monozygotic twins DZ = Dizygotic twins Concordances for ASD from Lichtenstein et al (2010) Review articles: Ronald & Hoekstra (2011) Autism Spectrum Disorders and Autistic Traits: A Decade of New Twin Studies. Neuropsychiatric Genetics, 156, Posthuma & Polderman (2013). What have we learned from recent twin studies about the etiology of neurodevelopmental disorders? Current Opinion in Neurology, 26,

11 Etiology of autistic traits The etiology of autistic traits does not differ across the distribution of severity 3000 Cast scale (0-31) N Total raw score Ronald et al (2006) Journal of the American Academy of Child and Adolescent Psychiatry Robinson et al (2011) Archives of General Psychiatry Lundstrom et al (2012) Archives of General Psychiatry

12 The relationship between autistic traits and autism Ø Genetic link between autism and autistic traits 3000 Cast scale (0-31) Ø Same environmental risk factors for autism and autistic traits e.g. birth complications N Total raw score Lundstrom et al (2012) Archives of General Psychiatry Robinson et al (2011) Archives of General Psychiatry Ronald et al (2006) Journal of the American Academy of Child and Adolescent Psychiatry Ronald et al (2010) Child Development Ronald et al (2011) Frontiers in Developmental Psychology

13 The relationship between autistic traits and autism Ø Characteristics of autism in general population (see original work by S. Baron-Cohen, D. V. M. Bishop, J. N. Constantino, D. H. Skuse) 3000 Cast scale (0-31) Ø Family members show elevated autistic traits (e.g. Bishop et al., 2006; Bolton et al., 1994) Ø Specific aberrant cortical structure similar for autism and autistic traits (Wallace et al 2012 Journal of Neuroscience) N Total raw score

14 Understanding nonshared environment from differences in monozygotic twins Ronald et al (2010) Child Development Wong et al (2013) Molecular Psychiatry and the forthcoming RATSS study!

15 Autism and Birth Complications Cause or Consequence?

16 Differences within MZ pairs discordant for birth problems Ronald et al (2010) Child Development N = 63 pairs

17 Autism and Epigenetics An Environmental Risk?

18 Childhood Autism Spectrum Test (CAST) ASD diagnoses assigned using Diagnostic Wellbeing Assessment (DAWBA) Whole blood DNA and RNA (controlled for blood cell counts) at age 15, buccal DNA age 5, 12, 15 Parental DNA ASD MZ Twin Samples Diagnostic Group No of MZ twin-pairs No of Individuals MZ twins discordant for: Diagnosed ASD 6 12 Social Autistic Symptoms 9 18 Non-social Autistic Symptoms 9 18 Communicative Impairments 8 16 MZ twins concordant for: Diagnosed ASD 5 10 Slides from Chloe Wong Low CAST scores (controls) TOTAL 48 96

19 ASD MZ Twin Study (P<2.2E 16) Distinctive patterns of DNA methylation associated with both autism diagnosis and related behaviour traits, and increasing severity of symptoms Wong et al (2013) Molecular Psychiatry

20 ASD MZ Twin Study Wong et al (2013) Molecular Psychiatry

21 An Etiological Continuum Au'sm spectrum disorders show high heritability Nonshared environment is significant but vital to assess its role independently of gene'c influences Au'sm and au's'c traits appear to lie on a quan'ta've phenotypic and e'ological con'nuum

22 Outline 4. Clues from Comorbidity 1. An Etiological Continuum 3. The Fractionable Autism Triad 2. Female Risk

23 Female Risk

24 Is there evidence for different phenotypic presentations in girls with ASD?

25 Sample Characteristics Nguyen & Ronald (Submitted)

26 Results No significant sex differences on autism symptoms, sensory over-responsivity, or behaviour problems Nguyen & Ronald (Submitted)

27 Do females with ASD have a greater burden of risk factors? Robinson, Lichtenstein, Anckarsäter, Happé & Ronald (2013). Proceedings of the National Academy of Sciences Commentary: Werling & Geschwind (2013). Proceedings of the National Academy of Sciences

28 Increase in risk to Siblings siblings of Female of female Probands probands Mean sex-and-zygositynormed Z scores Siblings of All Non-Probands n(teds)= 3,444 n(catss)=5,340 Siblings of Male Probands n(teds)= 262 n(catss)=470 Siblings of Female Probands n(teds)= 136 n(catss)= TEDS CATSS Combined Cohorts P< P< P< P=0.002 P=0.024 P< Robinson et al (2013). Proceedings of the National Academy of Sciences Commentary: Werling & Geschwind (2013). Proceedings of the National Academy of Sciences

29 Autism in females Robinson et al (2013). Proceedings of the National Academy of Sciences Commentary: Werling & Geschwind (2013). Proceedings of the National Academy of Sciences

30 Outline 4. Clues from Comorbidity 1. An Etiological Continuum 3. The Fractionable Autism Triad 2. Female Risk

31 Bivariate twin model r e r c r g E C A A C E Trait 1 Trait 2

32 Genetic correlation (r g ) 0 1

33 Genetic correlation (r g ) 0 1 If r g = 0, there are no common genetic influences across two traits

34 Genetic correlation (r g ) 0 1 If r g = 1, all the genes influencing the two traits are completely overlapping. At the genetic level, these two things are the same

35 Genetic correlation (r g ) r g = 0.5, some genes are overlapping between the two traits, and some are specific to each

36 Nonshared environmental correlation (r e ) r e = 0.5, some environments are overlapping between the two traits, and some are specific to each

37 Autistic symptoms may have different causes r ph = phenotypic correlation Social r g = genetic correlation r ph =? r g =? r ph =? r g =? Communication r ph =? r g =? Restricted Repetitive Behaviours & Interests

38 Weak links between autistic traits Social male/ female r ph =.39/.26 r ph =.27/.17 Communication r ph =.42/.34 Restricted Repetitive Behaviours & Interests Ronald, et al (2006a,b) Journal of the American Academy of Child & Adolescent Psychiatry See also: Ronald et al (2005) Dev Science; Ronald, et al (2010) Mol Psych; Robinson et al (2012) Beh Gen

39 Modest genetic overlap between different autistic traits Social male/ female r g =.39/.29 r g =.31/.18 Communication r g =.50/.42 Restricted Repetitive Behaviours & Interests Ronald et al (2006a, b) Journal of the American Academy of Child & Adolescent Psychiatry See also: Ronald et al (2005) Dev Science; Ronald, et al (2010) Mol Psych; Robinson et al (2012) Beh Gen

40 Fractionable Autism Triad Hypothesis Social Communication Restricted Repetitive Behaviours & Interests Happé, Ronald & Plomin (2006) Nature Neuroscience Happé & Ronald (2008) Neuropsychology Review Robinson et al (2012) Behavior Genetics Commentary: Mandy & Skuse (2008) J Child Psychol Psychiatry

41 Outline 4. Clues from Comorbidity 1. An Etiological Continuum 3. The Fractionable Autism Triad 2. Female Risk

42 Comorbidity in ASD ASD+Social Anxiety ASD ASD+ADHD ASD Ø 70% have at least one comorbid disorder Ø 40% have two or more comorbid disorders Simonoff et al (2008) J American Academy Child & Adolescent Psychiatry

43 Twin studies on co-occurring psychopathology Socialcommunication Restricted Repetitive behaviours and interests Internalising traits Language problems Tic disorder ADHD Low cognitive ability/ learning disorders Psychopathic tendencies Developmental coordination disorder Clumsiness See reviews by Ronald & Hoekstra (2011); Posthuma & Polderman (2013)

44 Autism and ADHD

45 Twin study on ASD and ADHD comorbidity 6107 twin pairs Mean age 7.88 years (SD=.53) Parent and teacher report Ronald et al., (2008) Journal of Child Psychology & Psychiatry

46 2000 Autistic traits r = (all p<.001) 1200 ADHD behaviours N N Cast Total score (0-31) Childhood Asperger Syndrome Test (Scott et al., 2002) Diagnostic and Well Being Assessment (Goodman et al., 2000) Conners Total score (0-54) Conners DSM-IV symptom scales (Conners et al., 1998)

47 Substantial genetic overlap with ADHD in 8-year-olds Traits in the population.19/.16.60/.55 Categorical diagnoses E A A E E A A E.21/.21.79/.79.86/.83.14/ Autistic traits ADHD traits ASD ADHD Male/female Ronald et al., (2008) Journal of Child Psychology & Psychiatry

48 Genetic Hypothesis Genes that influence ASD but not ADHD behaviours ASD ADHD Genes that influence ADHD but not ASD behaviours Genes that are common to both

49 Converging evidence for overlap in gene'c influences Age 2 (parent report) r g =.27 Ronald et al., 2010 Age 8 (parent/teacher) r g = Ronald et al., 2008 Age 12 (parent report) r g = Taylor et al., 2013 Age r g =.72 (self report) Reiersen et al., 2008 See also Lundstrom et al., 2011 and Polderman et al., 2013

50 Evidence for overlap in environmental influences Age 2 (parent report) r e = -.17 Ronald et al., 2010 Age 8 (parent/teacher report) Age 12 (self report) r e = r e = Ronald et al., 2008 Taylor et al., 2013 Age (self report) r e =.26 See also Lundstrom et al., 2011 and Polderman et al., 2013 Reiersen et al., 2008

51 But what about specific symptoms?

52 i) ii) iii) iv) Ronald, Larsson, Anckarsäter & Lichtenstein (Under review)

53 Ronald, Larsson, Anckarsäter & Lichtenstein (Under review)

54 But what about development?

55 Autistic traits and ADHD traits: Longitudinal relationship? A A C CAST 8 CAST 12 C E E A A C Conn 8 Conn 12 C E E Taylor et al (2013) Psychological Medicine

56 Autistic traits and ADHD traits: Longitudinal relationship? A A C M=0.12 F=0.16 CAST 8 M=0.50 F=0.47 CAST 12 M=0.11 F=0.11 C E E M=1 F=1 M=1 F=1 A A C M=0.18 F=0.15 Conn 8 M=0.63 F=0.61 Conn 12 M=0.15 F=0.22 C E Taylor et al (2013) Psychological Medicine E

57 ASD + ADHD: Why? Family studies - - shared familial influences (Mulligan et al., 2008; Nijmeijer et al., 2009) Twin studies - - overlapping gene'c and environmental influences (Constan'no et al., 2003; Reiersen et al., 2008; Ronald et al., 2008, Ronald et al., 2010; Lundstrom et al., 2011; Polderman et al., 2013) Models support the conceptual dis'nc'on of ASD and ADHD, while also showing significant symptom- specific e'ological influences ASD and ADHD traits influence each other across development (Taylor et al., 2013)

58 Large-scale genetic study identifying pleiotropic genes GWAS, genome-wide association study Smoller et al (2013) Lancet

59 Calcium channel signalling genes Smoller et al (2013) Lancet

60 Genes and environment influence risk for autism and evidence supports an etiological continuum with autistic traits 2. New empirical evidence supports a female protective effect against autism 3. Different symptoms within autism appear to have different causal pathways 4. Behaviour genetic research on comorbidity informs our understanding about the causes of autism

61 Autism Everyone else

62 The Autisms e.g. Abrahams & Geschwind (2008)

63 CIs SYMPTOMS SIs RRBIs e.g. Ronald et al (2006, 2010)

64 Autism Autism e.g. Robinson et al (2013)

65 ADHD Depression Autism Anxiety Sleep problems e.g. Ronald et al (2008); Lundstrom et al (2011)

66 Autism Everyone else e.g. Ronald et al (2006); Lundstrom et al (2011)

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69 Acknowledgements Collaborators: Professor Philip Asherson Professor Henrik Anckarsäter Professor Simon Baron-Cohen Professor Patrick Bolton Professor Tony Charman Dr Katharina Dworzynski Dr Lisa Edelson Professor Francesca Happé Dr Rosa Hoekstra Dr Jonna Kuntsi Dr Henrik Larsson Professor Paul Lichtenstein Dr Emma Meaburn Professor Jon Mill Ms Camilla Nguyen Dr Thomas Price Professor Robert Plomin Dr Elise Robinson Dr Kim Saudino Dr Leo Schalkwyk Professor Emily Simonoff Mr Mark Taylor Professor Andrew Whitehouse Dr Chloe Wong Many thanks to the TEDS team, the CATSS data managers, the Boston University Twin Project, and the participating schools Gratefully acknowledge the participants of TEDS, CATSS and BUTP Thank you to Professor Sven Bölte and everyone at KIND for the visit today

70 Thank you