Genetic Contributors to Alcohol Use and Misuse in Young People

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1 Genetic Contributors to Alcohol Use and Misuse in Young People Marianne BM van den Bree Professor of Psychological Medicine Institute of Psychological Medicine and Clinical Neurosciences MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University School of Medicine United Kingdom

2 Alcohol Statistics Part of the enjoyment and social fabric of life However, rates of misuse high, particularly in the young 13% of 15 year olds in Britain drunk >= 10 times past year 1% drink nearly every day Misuse attributed to: ~50% of deaths of young people Homicides, suicides and vehicle accidents ~40% of A&E attendance in Britain Other negative consequences E.g., delinquency, hazardous driving, risky sexual behaviour

Alcohol Misuse and the Adolescent Brain Major changes take place in the adolescent brain Increase in connections between brain cells (neurons) Changes in the strength of communication Alcohol misuse

3 Alcohol Misuse and the Adolescent Brain Major changes take place in the adolescent brain Increase in connections between brain cells (neurons) Changes in the strength of communication Alcohol misuse can impact upon: Brain structure and function, even after months of abstinence White matter integrity; prefrontal, cerebellar and hippocampal volume; atypical brain activation Cognitive function Impaired learning, memory, attention, planning, problem solving Behaviour Behaviour may become more emotional than controlled and planned

4 Research Question 1 Is there evidence for genetic influences in adolescence on: Experimentation with alcohol? Problem use?

5 Cardiff Twin Study Funded by Genetic Influences 26% 64% Genetic Influences Experimentation with alcohol Progression to Problem Use Environm ental Influences 74% 36% Environm ental Influences Fowler, Lifford, Shelton, Rice, Thapar, Neale, McBride, and van den Bree: Addiction, 2007.

6 Research Question 2 Have specific genes been identified?

7 Biological Systems Genes involved in the breakdown of alcohol in the liver (metabolising genes) Genes involved in the rewarding effects of alcohol (reward pathway) Genes involved in stress regulation

Metabolising Genes Alcohol breakdown (oxidation) process Hang-over Ethanol Acetaldehyde Acetate ADH1B*47His allele Higher activity enzyme Alcohol Dehydrogenase (ADH) Aldehyde Dehydrogenase

8 Metabolising Genes Alcohol breakdown (oxidation) process Hang-over Ethanol Acetaldehyde Acetate ADH1B*47His allele Higher activity enzyme Alcohol Dehydrogenase (ADH) Aldehyde Dehydrogenase (ALDH) ALDH2 487Lys (ALDH2*2) allele Deficiency in ALDH2 activity Asian flush: nausea, rapid heart rate and flushing after drinking alcohol Protective factor in development of alcohol use disorder

9 The Reward Pathway in the Brain Necessary for survival Activated by rewarding activities (food, music, socializing, alcohol use)

(SLC6A4) Association learned between alcohol and feeling good Increased alcohol use to achieve same effect, craving and

10 The Reward Pathway: Excitatory neurotransmitter in the brain Role in motor control, emotion, motivation, impulse control, learning, memory Dopamine Experimentation Chronic use DRD1, DRD2, DRD4, COMT, MAO-A, Solute carrier family 6, member 4 (SLC6A4) Association learned between alcohol and feeling good Increased alcohol use to achieve same effect, craving and relapse Role of dopamine in reward pathway influenced by: Other neurotransmitters (GABA, Glutamate, serotonin, opioids) Stress regulation factors

The Reward Pathway: Other neuro-transmitters Gamma-aminobutyric acid Inhibitory neurotransmitter in the brain Role in seizures, anxiety and impulsivity

11 The Reward Pathway: Other neuro-transmitters Gamma-aminobutyric acid Inhibitory neurotransmitter in the brain Role in seizures, anxiety and impulsivity Experimentation Chronic use GABA GABA Relaxed, disinhibited, drowsy Hyperexcitability, anxiety, stress Increased risk of relapse GABA A receptor, alpha 2 (GABRA2) & 6 (GABRA6)

The Reward Pathway: Other neuro-transmitters Excitatory neurotransmitter in the brain Essential for formation and survival of brain cells Too much or too little glutamate in brain can be

12 The Reward Pathway: Other neuro-transmitters Excitatory neurotransmitter in the brain Essential for formation and survival of brain cells Too much or too little glutamate in brain can be harmful Heavy Use Glutamate Withdrawal Glutamate Glutamate receptor, metabotropic 8 (GRM8) Alcohol-related learning problems and memory blackouts Hyperactivity, seizures and brain cell death

13 The Reward Pathway: Other neuro-transmitters Excitatory neuro-transmitter in the brain Role in body temperature regulation, sleep, appetite, impulse control, pain, mood, cognition Experimentation Serotonin Withdrawal Serotonin Feelings of happiness, optimism, willingness to take chances Low mood, anxiety, increased risk of relapse SLC6A4, HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3A, MAOA

14 The Reward Pathway: Other neuro-transmitters The endogenous opioid system Excitatory neurotransmitter in the brain Role in neuron growth, cognition, pain, stress response Experimentation Chronic use Beta endorphins Beta endorphins Opioid receptor, kappa 1 (OPRK1) Opioid receptor, mu 1 (OPRM1) Pleasure, well-being, relaxed, drowsy Low mood, stress Genetically determined low levels of beta endorphins Stronger reaction to stress Greater risk of developing alcohol use disorder

15 Stress Regulation Corticotropin-releasing factor (CRF) Adrenocorticotropin hormone (ACTH) Hypothalamic pituitary adrenal (HPA) axis (cortisol) Role in immune system, temperature regulation, learning and memory Chronic use/ Withdrawal CRF ACTH Cortisol Corticotropin-releasing hormone receptor 1 (CRHR1), GABRA6, OPRM1, SLC6A4 Brain reward pathway dysfunction, anxiety, depressed mood, craving Sensitivity to stress Genetically influenced Exposure to environmental stressors People more sensitive to stress at greater risk of alcohol use disorder Prolonged high stress levels can lead to brain changes Impaired decision making Increased risk of continued use and relapse

16 Research Question 3 Does the environment play a role in how risk genes exert their effect on alcohol experimentation/ misuse in adolescents (evidence for gene-environment interplay)?

17 Gene-Environment Interplay Social environment Higher genetic risk (G allele OPRM gene) High environmental risk Deviant peer group Low levels of parental monitoring Increased risk alcohol use disorder Stressful life events Higher genetic risk (C allele corticotropin releasing hormone receptor 1 (CRHR1)) Severe stressful life events e.g., childhood sexual abuse Heavier drinking in adolescence

18 Summary and Conclusions: Question 1: Evidence for genetic influences on experimentation and misuse? Yes, and genetic influences may be stronger for development of misuse compared to experimentation Question 2: Have specific genes been identified? The biology of development of alcohol use disorder is very complex A number of different systems are involved, which are interlinked and influence each other Evidence for the involvement of genes involved in: Breakdown of alcohol in the liver (metabolising genes) Reward pathway Stress regulation Major changes in the brain during adolescence Alcohol misuse may interfere long-term with reward and stress regulation systems Does the environment play a role in how risk genes exert their effect on alcohol misuse in adolescence? Yes, those at high genetic risk may be particularly sensitive to environmental risk (gene environment interaction) However, a protective environment can eliminate genetic risk E.g., non-deviant, supportive peer group; caring, involved parenting Implications for prevention and early intervention

19 Thank You!

processes in the central nervous system (CNS), affecting many of the during the course of ethanol treatment. Ethanol stimulates the release of

processes in the central nervous system (CNS), affecting many of the during the course of ethanol treatment. Ethanol stimulates the release of INTRODUCTION INTRODUCTION Neuroscience research is essential for understanding the biological basis of ethanol-related brain alterations and for identifying the molecular targets for therapeutic compounds