7/6/2017. Who we are. What we'll be talking about today. Sarah Medland Penelope Lind Katrina Grasby Jodie Painter

Transcription

1 Reviewing the role of genetics in psychological traits and psychiatric disorders QIMR Berghofer Medical Research Institute 1 Who we are Sarah Medland Penelope Lind Katrina Grasby Jodie Painter What we'll be talking about today What genetics can tell us about the aetiology of psychological traits & disorders Methods used in genetic research Looking at the literature What is the current state of knowledge Genetics in Psychological Practice Genetic testing Lack of resources QIMR Berghofer Medical Research Institute 3 1

2 Introduction to genetic methods Nature and Nurture Genetic Epidemiology is an interdisciplinary field aka Behavioural Genetics, Biological Psychology seeks to understand the genetic and environmental factors and how they interact to produce various diseases and traits provides a framework to talk about relative importance of causal factors Mainly used to establish heritability and is traditionally viewed as the first step to undertaking genetic work on a disease or trait. Heritability Some conceptualizations the proportion of phenotypic variance attributable to genetic variance. the extent to which individual differences in genomics contribute to individual differences in observed behaviour or disease QIMR Berghofer Medical Research Institute 6 2

3 Heritability a population concept not an individual one a heritability of.40 informs us that, on average, at a population level about 40% of the individual differences in a trait may in some way be attributable to genetic individual difference. It does NOT mean that 40% of an individual's trait is due to his/her genes and the other 60% is due to his/her environment. QIMR Berghofer Medical Research Institute 7 Heritability a population concept In the absence of trait OR genetic variation within a population heritability equals zero QIMR Berghofer Medical Research Institute 8 Heritability an abstract concept heritability estimates tell us nothing about the specific genes that contribute to a trait Measuring heritability values in two populations that show a difference in their means provides no information on whether the underlying difference is genetic depends on the range of typical environments in the population that is studied. QIMR Berghofer Medical Research Institute 9 3

4 Heritability is not a cause for therapeutic nihilism. heritability depends on the range of typical environments in the population studied, tells us little about the relative importance of genetic effect under the extreme environmental interventions utilized in some therapies. QIMR Berghofer Medical Research Institute 10 Heritability The methods for estimating heritability were originally developed for experiments on plant and animal breeding The application to behavioural processes has been controversial. On-going controversy over assumptions of the method QIMR Berghofer Medical Research Institute 11 Estimating Heritability QIMR Berghofer Medical Research Institute 12 4

5 Genotype Environment G r Latent variables E h e Measured variable P Phenotype Interactions and Correlations Mating system, population structure GxE interaction G E correlation Direction of Causation and Causal networks Remembering, Forgetting, Development (GxAge, GxTime etc.) Early work focused on familial resemblance Alice Lee 5

6 From Pearson and Lee (1903) p.377 & 378 However, nuclear family data alone can t distinguish the influence of shared familial environments from unshared/unique environment 6

7 Twins reared apart and together fraternal twins reared apart (DZA) fraternal twins reared together (DZT) identical twins reared apart (MZA) identical twins reared together (MZT) MZT share 100% of genes and environment MZA share 100% of genes only DZT share 50% of genes and environment DZA share 50% of genes only A = rmza = 2rDZA C= rmzt rmza E = 1-rMZT Minnesota Study of Twins Reared Apart Over 100 sets of reared-apart twins or triplets from around the world Age at separation from birth to 4.5 years median of.2 years Years from separation to first contact from 0 to 64 years median of 33.8 years Issues MZA and DZA are vanishingly rare in western societies Non-random placement Timing of adoption & reuniting 21 7

8 HTDEV2 HTDEV2 Adoption studies Does the behavior of the adopted child resemble the behavior of the biological parent or the adoptive parent? Largest Study was in Denmark by Sarnoff Mednick (14,427 adoptions) using the national registry data Best known Colorado Adoption Project John DeFries & Robert Plomin (2,400 adoptions) 22 Issues Need data from Adoptee, Biological & Adoptive parents Non-random placement Timing of adoption 23 Most common design in modern twin studies - MZ & DZ twins reared together Scatterplot for corrected MZ stature Scatterplot for age and sex corrected stature in DZ twins r= r= HTDEV1 HTDEV1 8

9 Classical twin study Identical (MZ) Twins Share 100% of their genes (A) During childhood and adolescence share the same home environment Share 100% of their common environment (C) Do not share unique environmental influences (E) Classical twin study Non-Identical (DZ) Twins On average share 50% of their genes the same as regular siblings During childhood and adolescence share the same home environment Assumed to share 100% of their environment Do not share unique environmental influences (E) CTD is often represented as a path diagram 1/.5 1 A C E A C E x y z x y z P-t1 P-t2 9

10 A additive genetic influences Sum of the average effects of individual alleles across the entire genotype. DZ twins & Siblings share 1/2 of the additive genetic variance because they receive the same alleles from their parents 1/2 of the time. Parent-offspring pairs also share 1/2 Half-sibs share 1/4 MZ twins share all of their additive genetic variance. C common environmental influences Sum of the average effects of individual shared exposures, experiences, perceptions and reactions (The impact of a shared event does not always end up as C it can also end up as E) E unique environmental influences Sum of the average effects of individual unshared exposures, experiences, perceptions and reactions Also measurement error 10

11 Assumptions of the basic CTD Equal environments between twin pairs The impact of MZs being treated more similarly than DZs does not influence the trait being studied No GEr (i) passive (e.g. books), ii) active (e.g. niche picking ), iii) evocative (e.g. aggression begets punishment) No G*E genes controlling sensitivity to the environment environment controlling gene expression No assortative mating No gene-gene interaction 1/.5 1 A C E A C E x y z x y z P-t1 P-t2 ACE Cov(mz) = a 2 + c 2 Cov(dz) = ½ a 2 + c 2 V P = a 2 + c 2 + e 2 Simultaneous Equations 11

12 Predicted Var-Cov Matrices Cov MZ a a Tw1 Tw2 Tw c e a c Tw2 2 c a c e Cov DZ Tw1 Tw2 Tw1 2 2 a c e a c 2 2 a Tw a c c 2 2 e 2 Structural Equation Modeling Use matrix algebra programs to estimate more informative (ie more complicated) models Find the best fitting model using likelihood ratio chi-square test Parameters are estimated not calculated Reported with 95% confidence intervals 12

13 What do we do once we establish heritability QIMR Berghofer Medical Research Institute Recruit a large sample 1. Recruit a large sample 2. Collect information from the sample 13

14 1. Recruit a large sample 2. Collect information on mental health from the sample 3. Collect a DNA sample 1. Recruit a large sample 2. Collect information on mental health from the sample 3. Collect a DNA sample 4. Genotype the samples 1. Recruit a large sample 2. Collect information on mental health from the sample 3. Collect a DNA sample 4. Genotype the samples 5. Look for genetic markers that can predict trait 14

15 What genetic markers are we talking about? QIMR Berghofer Medical Research Institute 43 DNA is composed of 4 nucleotide bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Genes are the basic physical and functional unit of heredity Genes are comprised of exons (coding) and introns (non-coding) surrounded by regulatory regions (e.g. promoters) DNA in exons is transcribed to RNA, which is then translated into a protein Genetic variation results from DNA nucleotide changes These changes are called variants, mutations, polymorphisms, single nucleotide polymorphisms (SNP) Alternative forms of a genetic variant are called alleles Each pair of alleles forms a genotype Homozygous genotype: A/A, G/G (identical alleles) Heterozygous genotype: A/G (differing alleles) 15

16 Mendelian traits are those that typically follow the one gene, one phenotype paradigm Mendelian mutations are both necessary and sufficient to cause the trait 900+ mutations identified in the PAH gene cause PKU Mendelian traits are typically uncommon, and follow clear patterns of inheritance e.g, Dominant inheritance: one mutated copy of the gene is sufficient for a person to be affected (Huntington disease) e.g., Recessive inheritance: two mutated copies of the gene are required for a person to be affected (cystic fibrosis and PKU) 16

17 6/07/2017 COMPLEX TRAITS AND DISEASES Diseases inherited as complex traits are often common in the population BMI, heart disease, mental health disorders Unlike Mendelian diseases, complex traits are influenced by multiple factors (multi-factorial): Genetic risk factors (multiple genes and genetic variants) Environmental risk factors CANDIDATE GENE STUDIES Traditional method to identify genetic variants that statistically associated with the trait of interest. Hypothesis driven approach - gene choice based on contemporary understanding of the biology of the trait, gene annotation and gene function. Limited to genotyping variants that could be easily captured by the existing technology within genes CANDIDATE GENE STUDIES Binary traits (case-control studies): e.g., alcohol dependence cases vs controls Testing for statistically significant differences in allele frequencies between cases and controls The size of effect is presented as Odds Ratios (OR) and P-value and is calculated for one allele (e.g., G for a G/T SNP) OR = increase in odds of being a case for each additional G allele OR>1: G allele increases risk of disease OR<1 : G allele is protective Comparable other effect size measurements e.g, Cohen's d = 0.2 (OR~1.4), 0.5 (~2.5) and 0.8 (OR>4) 1

18 6/07/2017 CANDIDATE GENE STUDIES Quantitative traits (e.g. symptom count, severity): Linear regression of the phenotype on the number of alleles for each variant For example, for a SNP with the alleles C/T, the trait would be regressed on to the number of T alleles Genotype C/C =0 T alleles, Genotype C/T=1, Genotype T/T=2 Effect size is presented as an unstandardised beta, SE and P-value Beta = how much the trait changes for each copy of the T allele CANDIDATE GENE STUDIES: LIMITATIONS Typically small sample sizes (N<500) and large ORs observed Biased selection of genes and genetic variants Gene choice based on current understanding of the biology of the trait and gene function Focus on variants in repeats and exons that modified protein structure and function Technology limitations + cost = small number of variants genotyped Genome-wide association studies (GWAS) with replication now gold standard (next session) CANDIDATE GENE STUDIES: LIMITATIONS Rarely replicated in follow-up studies Publication bias (file drawer problem) winner s curse - original effect sizes reported were overestimated leading to underpowered follow-up studies (sample sizes too small) Typically did not take multiple testing into account (P<0.05/#variants) 2

19 6/07/2017 Sample: 4,296 Australian twins of European ancestry (65.6% female) Phenotypes analysed: Alcohol consumption, DSM-IIIR AD Genes: 7 Alcohol Dehydrogenase genes (ADH1A, ADH1B, ADH1C, ADH4, ADH5, ADH6, ADH7) on chromosome 4 Gene function: Catalyse the oxidation of ethanol to acetaldehyde Hypothesis: Acetaldehyde is toxic and produces negative physiological reactions that reduce the rewarding effects of ethanol. Therefore, ADH genetic variants (SNPs) that result in an increase in the rate of alcohol conversion to acetaldehyde will reduce an individual s vulnerability to alcohol abuse and alcohol dependence. Genotyped 38 SNPs across region Study-wide significant associations (P < 2.3 x 10-4 ) observed with the exonic non-synonymous ADH1B-Arg48His SNP (rs ). A-allele (His48 variant, ~5% frequency) results in a 40-fold increase in ADH1B enzyme activity --> increased rate of acetaldehyde production The A-allele associated with: Higher prevalence of self-reported flushing after drinking alcohol (P= 8.2x10-7 ) Drinking alcohol less frequently (P= 2.7x10-6 ) Lower overall alcohol consumption in the previous 12 months (P= 8.9x10-8 ) ADH1B-Arg48His (rs ) is nominally associated with DSM-IIIR AD (P = ) A-allele (His48) is also protective for DSM-IIIR AD Odds ratio in males = (95% CI: ) Odds ratio in females = (95% CI: ) Allele Counts A G Cases Controls Allele Counts A G Cases Controls A G Cases a b OR = odds that A allele occurs in a case = a/c = a*d Cons c d odds that G allele occurs in a case b/d b*c 3

20 6/07/2017 IN SUMMARY Very few robust findings from candidate gene studies Be aware of the limitations when discussing genetic findings with clients Reported effect sizes are typically overestimated (publication or ascertainment bias) and sample specific ( winners curse ) Genetic findings can be ancestry specific (e.g., ALDH2) IN SUMMARY Biological effects of genetic variants are often unknown or poorly understood. Genetic variants increase risk but are not causal (cf Mendelian diseases) and the environment is also important. Candidate gene studies are limited by our current knowledge of genetics and disease biology now supplanted by genome-wide approaches. STUDYING COMPLEX TRAITS IS COMPLICATED Complex traits are polygenic Multiple genetic variants in multiple genes Each variant typically has a small effect (OR<1.1, Cohen s d ~0.05) or explain a small proportion of phenotypic variance (<1%). e.g., 97 independent BMI-associated loci (P < ) only account for ~2.7% of BMI variation [Locke et al. Nature 2015] By comparison, sex explains 1% and age explains 5.6% of variation in BMI On average, each risk allele was associated with an increase of g increase for an individual cm in height (0.1 BMI units) Multiple types of interplay between environmental factors and genetic predisposition e.g., environmental exposures in the same causal pathway (ADH genes --> alcohol consumption --> throat cancer) 4

21 6/07/2017 GENE-BY-ENVIRONMENT INTERACTION Gene-by-environment interaction (GxE) is the most studied 1. Genetic vulnerability predisposes an individual to the development of a psychiatric disorder when exposed to adversity (diathesis-stress model) e.g., adult depression and childhood maltreatment (Caspi et al. Science 2003) GENE-BY-ENVIRONMENT INTERACTION 2. Genotype can exacerbate an individual's risk of psychopathology in negative environmental conditions. They can also mitigate the risk of psychopathology in positive environmental conditions (differential-susceptibility perspective) Classic example is the 2003 Caspi et al GxE study published in Science Dunedin Multidisciplinary Health and Development Study (N=845 Caucasian non-maori participants) An increasingly positive relationship between number of self-reported stressful life events and depression risk among individuals having more short alleles at the serotonin transporter (5-HTTLPR) polymorphism The short (s) allele (43% allele frequency) is associated with lower expression of the gene. Long (l) alleles were protective 5

22 6/07/2017 Created a lot of media, science and policy attention (e.g., NIH created a special call to fund research following up this finding ~US$3-4 million spent) Few studies have replicated this finding. Why? Meta-analysed all GxE papers published between (N=103) Majority used a candidate gene-by-environment approach Evidence of publication bias against null results positive results reported in 96% (45/47) of novel G E findings, but only 27% (10/37) of replication attempts. Most were statistically underpowered due to small sample sizes -> increased false discovery rate The scale of the environmental stressor and outcome important EPIGENETICS Changes to DNA can also affect levels of gene expression, which affects how much/when protein is made Gene expression can be affected by multiple factors 1. Genetic variants e.g. A/G G allele gene expression EPIGENETICS 2. Epigenetics Factors above the genes do not involve changes in DNA bases Instead, other molecules interact with DNA to either enhance/activate or repress/abrogate gene expression Epigenetic processes occur throughout the life cycle: prenatal development through to adulthood 6

23 6/07/2017 EPIGENETIC PROCESSES DNA methylation: methyl group attached to C bases Typically permanent Histone protein modification: molecules added to the histone proteins around which DNA is packaged Can be permanent or transient Both types of changes can enhance or repress gene expression EPIGENETICS AND DISEASE Epigenetic processes can be influenced by the environment Diet Stress Toxins/pollution Pre-natal exposures (diet) Emerging evidence for a role in mental health (e.g. depression, schizophrenia, bipolar disorder) Animal model/candidate gene studies How these interact with genetic variants largely unknown How biological process predispose to disease also unknown Best advice at the moment is to live well 7

24 Genome Wide Association Studies (GWAS) Definition A genome-wide association study is defined as any study of genetic variation across the human genome. Motivations 1

25 In practice the same method as candidate gene association Case Control Differences from candidate gene approaches Hypothesis free approach Candidate gene approaches are often based on medication targets - False assumption that treatment targets cause the disease Identification of potential candidates can only ever be as good as the biological characterisation of the gene and the correct annotation in databases Differences from candidate gene approaches Based on the expectation that the trait under analysis is highly polygenic Exploratory mapping approach rather than a confirmatory style approach Genotypic data can be used to study other traits/diseases in the same population Increased emphasis of data and analysis quality 2

26 Example success story FTO gene and BMI GWAS for T2D discovered a significant hit in an unexpected region on chr 16 Subsequently discovered to be associated with obesity and BMI not diabetes FTO gene and BMI Huge effect Adults who are homozygous for the risk allele weigh about 6 kg more than those without risk alleles Obese individuals are 1.5 times more likely to have inherited risk genotypes than lean controls Replicates in most european samples But it never would have been a candidate gene (even though it was called the Fatso gene) Since renamed fat mass and obesity associated gene GWAS data provides an effective way of dealing with population stratification 3

27 GWAS data provides an effective way of dealing with population stratification Population stratification Take a trait where there is a mean or frequency difference between ethnicities + A genetic marker which shows allele frequency differences between ethnicities = Population stratification (more often than not) Compute principal components from the genotypic data and include these as covariates 4

28 Volume of data Typically genotype ~500k variants Using publically available reference sets impute to ~10 million variants Increased multiple testing burden Burden of proof is much higher than in candidate gene studies Based on the theory that the chips tag all common variation in the genome Bonferroni correction based on the number of independent tests ~ 1 million across the whole genome Usual significance threshold is 5*10-8 It doesn t matter if your chip has 300K or 3M snps Replication is also required to declare significance 5

29 Presenting results After GWAS Can use a full set of GWAS results to estimate SNP based heritability no relatives required Correlation between 2 traits due to shared genetic influences Effect sizes of individual variants are very small typically explain < 0.2% of variance But cumulative effects can be much larger Polygenic risk scores 6

30 Utility of results Clinical Usefulness Factors to consider Accuracy Sensitivity Specificity Interpretability Availability Cost Personalised treatment? Prediction Accuracy Test Disorder No Disorder Predictive Value (PV) Positive True +ve False +ve Positive PV True +ve / All positive tests Negative False -ve True -ve Negative PV True ve / All negative tests Sensitivity Specificity True +ve True -ve All with disorder All without disorder Challenges in genetics Polygenicity ( sensitivity) Pleiotropy ( specificity) 7

31 Example Alzheimer s Disease AUC of.78 including PRS (P<0.5), APOE, age & sex. (Escott-Price et al. 2015) Compare with BDI-II Cutoff Sensitivity Specificity PPV NPV AUC %MDD Non-clinical sample Gorenstein Shean & Baldwin ? 17.9 Medical sample Arnau Bunevicius Low & Hubley Williams Stepping Stones to Treatment Clozapine proven efficacy BUT haematological side-effect regular monitoring & under-prescription Aetiology unknown 8

32 A test including 3 variants (rs , rs , rs ) Sensitivity 29.17% Specificity 90.61% Positive predictive value only 9.94% Negative predictive value of 97.30% QIMR Berghofer Medical Research Institute 25 Discussion What level of predictive accuracy would be acceptable? How important is cost? Cost of testing Cost of treating or not treating What is the role of severity of disease or sideeffects when considering the costs and benefits and accuracy? Considering the complexity psychological disorders, how achievable is interpretability? 9

33 Current results and how to read the papers Where to find these papers QIMR Berghofer Medical Research Institute 2 Many free versions of these papers QIMR Berghofer Medical Research Institute 3 1

34 Many free versions of these papers QIMR Berghofer Medical Research Institute 4 QIMR Berghofer Medical Research Institute 5 Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (130,664 MDD cases and 330,470 controls) No social media posting QIMR Berghofer Medical Research Institute 6 2

35 QIMR Berghofer Medical Research Institute 7 QIMR Berghofer Medical Research Institute 8 QIMR Berghofer Medical Research Institute 9 3

36 QIMR Berghofer Medical Research Institute 10 QIMR Berghofer Medical Research Institute 11 Important things to consider in reading GWAS papers 1 Sample size Be wary of any paper with less than 1,000 cases and 1,000 controls For a continuous phenotype look for ~2,000 individuals minimum Family based data is fine as long as the authors use an analysis method that accounts for relatedness 4

37 Important things to consider in reading GWAS papers 3 Confounders any variable in the study which could be different between cases and controls other than the disease itself Ethnicity, access to medical treatment and diagnosis, urban/rural Important things to consider in reading GWAS papers 4 Replication Is essential independent samples 5 Biology Take claims regarding the biology and importance of the gene/region with a large dose of salt! 6 Supplementary Most of the important information is not in the paper, it is in the suplementary! Important things to consider in reading GWAS papers 7 Authorship 5

38 Reading the Literature Demographics Ancestry Ascertainment Replication Significance Sample size Effect size Final sample size QIMR Berghofer Medical Research Institute 17 Intro QIMR Berghofer Medical Research Institute 18 6

39 Discovery sample, size & ancestry Ascertainment QIMR Berghofer Medical Research Institute 19 Replication sample Final Sample size & Key finding QIMR Berghofer Medical Research Institute 20 QIMR Berghofer Medical Research Institute 21 7

40 Lots on test statistic inflation why polygenicity & not population stratification QIMR Berghofer Medical Research Institute 22 Where in the variants are in the genome QIMR Berghofer Medical Research Institute 23 QIMR Berghofer Medical Research Institute 24 8

41 Enrichment QIMR Berghofer Medical Research Institute 25 QIMR Berghofer Medical Research Institute 26 PRS = RPS Effect sizes Odds Ratio & ascertainment QIMR Berghofer Medical Research Institute 27 9

42 AUC QIMR Berghofer Medical Research Institute 28 QIMR Berghofer Medical Research Institute 29 QIMR Berghofer Medical Research Institute 30 10

43 Example Paper, Schizophrenia Significance p < 5e-8 Sample size Cases 36,989 Controls 113,075 Effect size not discussed for individual loci Risk score explains ~7% of variation in liability Odds Ratio for 10 th decile of risk score were 7.8, 15.0, and 20.3 for population, hospitalisation, and genetic study ascertainment samples respectively AUC only.62 for the population sample Group paper Look for Sample size Ancestry Ascertainment Significance Effect sizes Polygenic risk scores Follow up Discrepancies with the media coverage Media on Educational Attainment It's all in the genes: How your parents can make you stay at school longer The Age Genetic differences explain just 3.2% of the variation in educational achievement between people. -Nature News research had reached a tipping point where tests would be used to identify people s individual strengths and weaknesses. The Guardian Scientists found 74 genetic variants linked to education level but their impact is minuscule Looking for genetic effects 'seems pointless -The Verge the researchers were able to identify many more loci that appear to contribute to cognitive ability than had been previously known because of the large number of participants. Science Direct 11

44 Genetics in Psychological Practice What types of situations Questions about heritability Questions surrounding genetic testing Pre-test Clients seeking tests Making decisions about testing Post-test Anxiety while waiting Interpreting results Dealing with the outcomes Incorporating this information into treatment planning QIMR Berghofer Medical Research Institute 2 Clinical Genetics Services Typically Schizophrenia, Intellectual Disability & ASD Usually provided in a clinical context that is meant to be able provide counselling Clients may present with concerns around Having a test done Anxiety during waiting periods Consequences of results Outcomes and implications for treatment Fatalistic/Deterministic attitudes QIMR Berghofer Medical Research Institute 3

45 Prenatal testing Typically provided in a clinical context that should be able to provide counselling QIMR Berghofer Medical Research Institute 4 QIMR Berghofer Medical Research Institute 5 QIMR Berghofer Medical Research Institute 6

46 Clients may present with concerns around Having a test done Anxiety during waiting periods Decisions following unexpected results QIMR Berghofer Medical Research Institute 7 Direct to consumer testing - can be very problematic For example this one currently being sold via chemists QIMR Berghofer Medical Research Institute 8 Idea: Genetic variations may predict a patient is at increased risk of experiencing the side-effects of certain drugs because they metabolise it slowly and high concentrations can build up on a normal dose. QIMR Berghofer Medical Research Institute 9

47 QIMR Berghofer Medical Research Institute 10 Sort of sounds ok but... The 'doctor' can be the pharmacist They are testing 2 genes influencing metabolism of SSRIs Each of these genes have hundreds of variations There are dosing recommendations but only for the common variations a normal test doesn t rule out side-effects or nonresponding Current tests only capture known variants of known genes. Many factors influence drug response including interactions with other drugs, allergies, and kidney and liver function. QIMR Berghofer Medical Research Institute 11 Example of guidelines CYP2C19 & Sertraline ~3% of Europeans ~20% of Europeans QIMR Berghofer Medical Research Institute 12

48 QIMR Berghofer Medical Research Institute 13 Other direct to consumer QIMR Berghofer Medical Research Institute 14 In UK and US it also provides health information QIMR Berghofer Medical Research Institute 15

49 QIMR Berghofer Medical Research Institute 16 Followup industry Multiple sites offering to interpret 23andMe results QIMR Berghofer Medical Research Institute 17 Unforeseen consequences of genetic testing Survivor guilt among those who screen negative in families with an inherited disease Depression & Anxiety relating to family members Frustrations about having a diagnosis for which there might be no treatment Difficulties accessing services or specalists Due to lack of resources Change in classification - NDIS & gov depts QIMR Berghofer Medical Research Institute 18

50 Consequences of ancestry testing QIMR Berghofer Medical Research Institute 19 QIMR Berghofer Medical Research Institute 20 Resources (or lack there of) QIMR Berghofer Medical Research Institute 21

51 Clinical Genetics Services Each state has it's own system Will need a doctor's referral Are unlikely to have expertise in mental health QIMR Berghofer Medical Research Institute 22 Genetic counsellors Are not actually trained in mental health or traditional counselling Masters program only available at 2 universities in Australia Both full time on-campus Small intake Psychology degree (Hons/Masters/PhD) is not a sufficient prerequisite QIMR Berghofer Medical Research Institute 23 Few and far between Australasian Society of Genetic Counsellors provides certification of genetic counsellors in Australia and New Zealand over 280 members across Australia and New Zealand Even if all Australian GCs undertook training in mental health conditions, there would not be enough GCs to respond to the growing number of requests for this type of information. QIMR Berghofer Medical Research Institute 24

52 Few and far between Australasian Society of Genetic Counsellors provides certification of genetic counsellors in Australia and New Zealand over 280 members across Australia and New Zealand Even if all Australian GCs undertook training in mental health conditions, there would not be enough GCs to respond to the growing number of requests for this type of information. In 2013 in Australia, there were an estimated 2,977 registered Psychiatrists 23,144 registered Clinical Psychologists QIMR Berghofer Medical Research Institute 25 One approach to this problem QIMR Berghofer Medical Research Institute 26 Provision of counselling reduced anxiety and perceptions of guilt Participants also reported increased perceived control, ability to cope and hope. The majority of participants had over-estimated the chances that other family members might become affected All participants indicated that the genetic counselling session had helped them understand that the risk faced by family members was less than they had expected.

53 Runs short courses on psychopathology for GC QIMR Berghofer Medical Research Institute 28 Runs short courses on psychopathology for GC QIMR Berghofer Medical Research Institute 29 Alternative solutions? QIMR Berghofer Medical Research Institute 30

54 (My personal option) The themes discussed in a Psychiatric Genetic Counselling session include current knowledge about the aetiology of disorder the known environmental risk factors how reducing and avoiding these risk factors can help resolve illness and prevent relapse. Involve psychologists QIMR Berghofer Medical Research Institute 31 (My personal option) Three key misconceptions that Psychologists are well placed to discuss with clients genes generally produce inevitable outcomes biological causes unequivocally equate to biological interventions the effects of genes are permanent QIMR Berghofer Medical Research Institute 32 What do you think? QIMR Berghofer Medical Research Institute 33