What can genetic studies tell us about ADHD? Dr Joanna Martin, Cardiff University

Transcription

1 What can genetic studies tell us about ADHD? Dr Joanna Martin, Cardiff University

2 Outline of talk What do we know about causes of ADHD? Traditional family studies Modern molecular genetic studies How can we translate genetic studies for clinical practice & education? Many clinically meaningful questions can be addressed using genetic studies Summary & future research

3 What is known about the causes of ADHD? Genes? ADHD Environment?

4 Types of genetic studies Traditional study designs Twin, family & adoption studies Indirect: genetic contributions are statistically inferred based on different degrees of relatedness Modern molecular genetic studies Genotyping & sequencing Direct measures of DNA changes

5 Studies of families & twins Familial aggregation study 1,656,943 Swedish individuals Increased risk of ADHD with increasing relatedness Twin studies Heritability: 70-80% Shared environmental factors are of limited importance Key references: Chen et al, 2016, JCPP; Faraone & Larsson 2018, Molecular Psychiatry

6 Molecular genetic studies Candidate gene studies GWAS CNVs SNVs Linkage studies

7 Genome-wide association study (GWAS) 20,183 ADHD cases 35,191 control individuals 8,047,421 variants Key reference: Demontis et al, In Press, Nature Genetics

8 ADHD GWAS results 12 associated regions Risk distributed across genome Tip of the iceberg 22% risk explained in total Important clues for biology DUSP6 dopamine FOXP2 language Brain-expressed genes Key reference: Demontis et al, In Press, Nature Genetics

9 Copy number variants (CNVs) Duplications or deletions of DNA Typically 2 copies; more (3+) or fewer (1/0) copies Larger & rarer CNVs are more likely to be pathogenic Larger CNVs affect more genes People with ADHD are more likely to have CNVs than healthy controls Especially neuropsychiatric CNVs Schematic illustration of CNVs: duplication (left) and deletion (right) Key reference: Williams et al, 2010, Lancet

10 Exome sequencing Very rare single nucleotide variants PTVs: Protein-truncating variants (aka loss-of-function mutations) DMMs: Damaging missense mutations Disrupt gene function People with ADHD (N=2,642) are more likely to have PTVs & DMMs compared to healthy controls (N=5,214) Key reference: Satterstrom et al, under review, available on biorxiv

11 Molecular genetic studies GWAS CNVs SNVs Common (frequency 1%) Rare (frequency < 1%)

12 Common vs. rare variants Common: small effect size Rare: larger effect size

13 Interim summary & key points ADHD is highly heritable Similar to other psychiatric disorders Emerging evidence that both common & rare genetic risk factors are implicated in ADHD ADHD is very complex There is not a single ADHD gene 1,000s or even 10,000s of genetic risk factors

14 So what can genetic studies tell us about ADHD?

15 Translating genetic findings Biology Medicine Genetic risk factors Outcomes in people Risk prediction Diagnosis & screening Clinical practice & education

16 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

17 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

18 Frequency How do we define ADHD? The extreme end of a distribution of traits in the population? Or is the disorder categorically & qualitatively different from traits? Twin studies Genetic risk Mild & more severe levels of symptoms show similar genetic effects Unaffected Affected Trait Distribution Key references: Levy et al, 1997, JAACAP; Larsson et al, 2011, JCPP

19 How do we define ADHD? Genetic risk scores in the population Very high common variant genetic correlation Rare CNVs impact on broadly-defined ADHD Key points Similar for other psychiatric disorders ADHD behaves both as a (autism, dimension depression) & a category Diagnoses are useful for categorical decisions Sub-threshold traits may also be clinically important Genetic risk for ADHD diagnosis ADHD traits Key references: Martin et al, 2014, Biol Psych; Demontis et al, In Press, Nature Genetics; Martin et al, 2018, Neuropsychiatric Gen

20 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

21 Is ADHD a neurodevelopmental disorder? Similarities but also differences Onset during infancy or childhood Neuropsychological impairments Higher prevalence in males Mainly non-episodic (i.e. no remissions & relapses) Notable treatment differences (e.g. stimulants for ADHD, antipsychotic medication for tic disorder) Why does ADHD overlap with other NDs? Key reference: Thapar, Cooper & Rutter, 2017, Lancet Psychiatry ASD Tics ADHD LD Motor

22 Is ADHD a neurodevelopmental disorder? Shared genetic risk factors Twin studies Multi-generation family studies Swedish registry (1.9M individuals) Autism spectrum disorder Intellectual disability Key references: Lichtenstein et al, 2010, Am J Psych; Ghirardi et al, 2017, Mol Psych; Faraone et al, 2017, JAACAP

23 Is ADHD a neurodevelopmental disorder? Rare known syndromes (e.g. VCFS, Fragile X, Tuberous Sclerosis) Same regions of the genome affected by CNVs in ADHD, ASD & ID Rare mutations (PTVs) occur in the same set of genes in ADHD & ASD Common variant genetic correlation for ADHD & ASD: r=0.36 ID genes Shared genes ADHD genes ASD genes Key references: Williams et al, 2010, Lancet; Satterstrom et al, under review; Grove et al, In Press, Nature Genetics

24 Is ADHD a neurodevelopmental disorder? Key points Shared biology could explain comorbidity across different NDs Affects diagnostic changes ADHD now considered & grouped as a ND ASD no longer an exclusion criterion Children with ID often also have ADHD Child neurodevelopmental clinics instead of separate ADHD and ASD clinics in Wales

25 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

26 Why do more boys have ADHD? Boys are 3-7 times more likely to be diagnosed Boys have higher levels of ADHD population traits Is ADHD biologically the same disorder in boys & girls? Are girls protected from developing ADHD? Do girls at genetic risk of ADHD develop other problems instead?

27 Why do more boys have ADHD? The same common genetic risk variants are equally important for ADHD in boys & girls Biologically the same disorder Family studies suggest that having a female relative with ADHD increases risk more than having a male relative Evidence is a bit mixed No evidence from molecular genetic studies Affected Higher risk Lower risk Key reference: Martin et al, 2018, Biol Psych

28 Why do more boys have ADHD? Are girls with ADHD missed from diagnosis? 1:1 ratio for ADHD in adult men & women Do girls at genetic risk of ADHD develop other problems instead? In children with diagnosed anxiety & depression, girls have a higher burden of common & rare variants increasing risk of ADHD Key references: Quinn & Madhoo, 2014, Prim Care Companion CNS Disord; Martin et al, 2018, Neuropsychiatric Gen

29 Why do more boys have ADHD? Key points ADHD is biologically similar in boys and girls Some families with affected girls might have higher genetic risk than families with affected boys protective effect? Girls at genetic risk of ADHD might be developing anxiety & depression instead Timely diagnoses in both genders are needed to help patients

30 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

31 Probability Persistence vs. remittance Why do some children grow out of ADHD while others have persistent problems? ADHD trajectories in the general population What is the difference between the childhood-limited & persistent groups? Low (82.6%) Intermediate (7.7%) Childhood-limited (5.8%) Persistent (3.9%) Age (months) Key reference: Riglin et al, 2016, JAMA Psychiatry

32 ADHD PRS Persistence vs. remittance Highest genetic risk in the persistent group Key point: Multi-morbidity (comorbidity with low IQ, autistic traits, language problems, conduct problems) Family history of ADHD ADHD is more likely to persist if an individual is at higher genetic risk Need to assess multi-morbidity in people with ADHD Low Intermediate Childhoodlimited Persistent Key reference: Riglin et al, 2016, JAMA Psychiatry

33 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

34 What about environmental risk factors? Does smoking in pregnancy cause ADHD? Natural experimental designs In-vitro fertilisation (IVF) Discordant sibling comparison Maternal vs. paternal exposure comparison Systematic review of 12 genetically informative studies No causal effect of smoking during pregnancy on ADHD Causal effect on lower birth weight & prematurity Key reference: Rice et al, 2018, Dev Psychopathol

35 What about environmental risk factors? ADHD shares genetic risks with smoking & many other environmental factors Key points Association causation Need to test for causality Familial/genetic confounding can explain some associations Key reference: Demontis et al, In Press, Nature Genetics

36 Questions we can address 1. What is the best way to define ADHD? 2. Should ADHD be considered as a neurodevelopmental disorder? 3. Why are more boys diagnosed with ADHD? 4. Why do some children grow out of ADHD while others have persistent problems throughout their lives? 5. Are there any environmental factors that increase risk of ADHD? 6. Can we use genetics to predict who will have ADHD?

37 Can we predict who will have ADHD? Genetic screening is already being used for ID and ASD in some severe cases to identify possible causes Given that rare variants are also important in ADHD, genetic testing might benefit people with ADHD too But risk variants are non-specific which makes prediction difficult

38 Can we predict who will have ADHD? Common genetic variants: collectively explain only 22% of ADHD risk Key points: Too weakly predictive for now Genetic testing will likely be feasible & helpful in the future Importance of genetic counselling Credit : Lauren Solomon, Broad Communications Key reference: Demontis et al, In Press, Nature Genetics

39 Translating genetic findings Biology Medicine Genetic risk factors Outcomes in people Risk prediction Diagnosis & screening Clinical practice & education

40 We need more ADHD genetic studies Sample sizes of ADHD genetic studies are smaller than for adult psychiatric disorders We need bigger genetic studies of ADHD to continue to do clinically-relevant research

41 Take-home messages (1) Genetic risk factors are very important for ADHD Highly heritable with limited evidence for environmental risks shared in families Ground-breaking new studies are beginning to identify specific genetic risk factors Follow-up needed to understand biology & to develop improved medications Not all environmental risk factors are truly environmental Shared genetic risks between ADHD & other population traits

42 Take-home messages (2) Genetic studies can address clinically meaningful questions ADHD can be viewed as a category & dimension Value of studying ADHD traits in the population ADHD & other NDs share genetic risks Might explain comorbidity Persistence of ADHD Higher genetic risks & multi-morbidity Importance of gender differences Girls at genetic risk of ADHD might develop anxiety & depression

43 ADHD genetics: what s next? Genetic studies can & will continue to be very informative for improving our understanding of ADHD Potential for: new treatments, personalised medicine, genetic testing & screening Epidemiology & causal mechanisms: need geneticallyinformed studies Examining sub-phenotypes and patient stratification We need more genetic studies of ADHD & long-term follow-up of patients

44 Acknowledgements

45 Useful resources