GENETIC INFLUENCES ON APPETITE AND CHILDREN S NUTRITION DR CLARE LLEWELLYN Lecturer in Behavioural Obesity Research Health Behaviour Research Centre, University College London Tuesday 8 th November, 2016 All-Island Obesity Action Forum Dublin, Ireland
HUMAN BODY WEIGHT HAS A STRONG GENETIC BASIS Identical twin pairs Non-identical twin pairs From: Borjeson (1976) Acta Paediatr Scand: 65; 279-87 Reviews: Elks et al (2012) Front Endocrinol:3;29; Min et al (2013) Obes Rev:14;871-82 ; Silventoinen et al (2010) Int J Obes:34;29-40
FAT MASS AND OBESITY ASSOCIATED GENE (FTO) Fraying et al (2007) Science: 316; 889-894
FTO AND BMI IN CHILDREN 0.3 0.25 0.242 0.2 0.15 0.1 0.073 0.05 0-0.05 TT AT AA -0.1-0.15-0.123 TT=36.2%, AT=49.2%, AA=14.6% Wardle et al (2008) J Clin Endocrinol Metab: 93; 3640-3
97 GENETIC VARIANTS ARE ROBUSTLY ASSOCIATED WITH BMI IN ADULTS AND CHILDREN For each unit increase in the genetic-susceptibility score (equivalent to 1 risk allele), BMI increases by 0.1 BMI units (kg/m 2 )/ 260 320g for an individual 160-180m tall. Difference in BMI between individuals with highest and medium numbers of risk alleles (>104) =1.8 OR 4.6 5.8 kg for an individual 160-180m tall. Combined impact of risk alleles on BMI and obesity; regression line of the mean BMI values across risk-allele scores From: Locke et al (2015) Nature: 518; 197-206
HOW? Obesity may arise as a result of increased energy intake, decreased energy expenditure or increased partitioning of nutrients into fat... It would be useful if we could reliably measure the extent to which each of these processes might be under genetic control in humans. O Rahilly & Farooqi; Phil Trans R Soc B; 2006 Professor Stephen O Rahilly
AN APPETITE PATHWAY FOR OBESTY GENES: BEHAVIOURAL SUSCEPTIBILITY TO OBESITY ENVIRON- MENT SOCIAL FACTORS e.g. food availability APPETITE POSITIVE ENERGY IMBALANCE e.g. high energy intake WEIGHT GAIN GENES METABOLIC FACTORS e.g. satiety hormones Llewellyn & Wardle (2015) Physiol Beh: 152; 494-501
AN APPETITE PATHWAY FOR OBESTY GENES: BEHAVIOURAL SUSCEPTIBILITY TO OBESITY Food responsiveness Satiety responsiveness Llewellyn & Wardle (2015) Physiol Beh: 152; 494-501
MEASURING APPETITE IN CHILDREN Carnell & Wardle (2007) Appetite: 48; 104-113
TWINS TELL US ABOUT NATURE AND NURTURE Identical twins are genetically the same; non-identical twins are 50% the same Both types of twins share their environments to a similar extent
Twin Correlation TWINS TELL US ABOUT NATURE AND NURTURE Intraclass correlations Maximum Likelihood Structural Equation Modelling 1 0.9 0.8 0.7 0.75 0.6 0.5 0.45 0.4 0.3 0.2 0.1 0 MZ DZ
16,000 families with twin births in 1994-96 5000 pairs assessed for anthropometrics and appetite at age 10 DNA Haworth, Davis, Plomin (2013) Twin Res Hum Genet: 16; 1-12
APPETITE AND ADIPOSITY ARE ASSOCIATED Satiety Sensitivity and BMI-SDS Satiety Sensitivity and Waist-SDS Carnell & Wardle (2008) Am J Clin Nutr: 88; 22-9
APPETITE AND ADIPOSITY ARE ASSOCIATED Satiety Sensitivity and BMI-SDS Food Responsiveness and BMI-SDS Satiety Sensitivity and Waist-SDS Food Responsiveness and Waist-SDS Carnell & Wardle (2008) Am J Clin Nutr: 88; 22-9
APPETITE IS HIGHLY HERITABLE, SUGGESTING AN APPETITIVE PATHWAY FOR OBESITY GENES 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 MZ (N=1919) DZ (N=3478) MZ (N=1928) DZ (N=3478) Food Responsiveness Satiety Responsiveness Carnell, Haworth, Plomin, Wardle (2008) Int J Obes: 32; 1468-1473
APPETITE IS HIGHLY HERITABLE, SUGGESTING AN APPETITIVE PATHWAY FOR OBESITY GENES 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 h 2 =0.75 (0.52, 0.85) h 2 =0.63 (0.39, 0.81) 0 MZ (N=1919) DZ (N=3478) MZ (N=1928) DZ (N=3478) Food Responsiveness Satiety Responsiveness Carnell, Haworth, Plomin, Wardle (2008) Int J Obes: 32; 1468-1473
SATIETY RESPONSIVENSS MEDIATES FTO S EFFECT ON ADIPOSITY Low risk Medium risk FTO GENOTYPE High risk Wardle, Carnell, Haworth, Farooqi, O Rahilly, Plomin (2008) J Clin Endocrinol Metab; 93:3640-3 Wardle, Llewellyn, Sanderson, Plomin (2009) Int J Obes; 33: 42-45
Number of individuals Mean age- and sex-adjusted phenotype score Number of individuals Mean age- and sex-adjusted phenotype score SATIETY RESPONSIVENESS MEDIATES THE ASSOCIATION BETWEEN MEASURED GENETIC RISK OF OBESITY AND ADIPOSITY 350 BMI-SDS: r = 0.18 0.6 350 Satiety Responsiveness: r = -0.06 0.6 Waist-SDS: r = 0.17 300 0.4 300 0.4 250 0.2 250 0.2 200 200 0.0 0.0 150 150 100-0.2 100-0.2 50-0.4 50-0.4 0-0.6 0-0.6 Number of weighted risk alleles Number of weighted risk alleles Llewellyn, Trzaskowski, van Jaarsveld, Plomin, Wardle (2013) JAMA Pedriatr; 168:338-44
Gemini Prospective birth cohort 2402 twin pairs born 2007 Anthropometrics: 3-monthly Appetite: 3 mths Van Jaarsveld, Johnson, Llewellyn, Wardle (2010) Twin Res Hum Genet: 13; 72-8
Llewellyn, van Jaarsveld, Johnson, Carnell, Wardle (2011) Appetite:57; 388-96
LARGE VARIATION IN INFANT APPETITE (BEBQ) Satiety Responsiveness Food Responsiveness Llewellyn, van Jaarsveld, Johnson, Carnell, Wardle (2011) Appetite:57; 388-96
PROSPECTIVE DATA SUGGEST SATIETY RESPONSIVENESS PLAYS A CAUSAL ROLE IN INFANT WEIGHT GAIN 2 4 6 8 10 12 0 3 6 9 12 15 Age (months) Weight trajectories of same sex DZ pairs discordant for satiety responsiveness (n=228 pairs; n=2671 observations) van Jaarsveld, Llewellyn Wardle (2014) JAMA Pediatr: 168; 345-50 van Jaarsveld, Llewellyn, Johnson, Wardle (2011) Am J Clin Nutr; 94:1562-7
PROSPECTIVE DATA SUGGEST FOOD RESPONSIVENESS PLAYS A CAUSAL ROLE IN INFANT WEIGHT GAIN 2 4 6 8 10 12 0 3 6 9 12 15 Age (months) Weight trajectories of same sex DZ pairs discordant for food responsiveness (n=228 pairs; n=2671 observations) van Jaarsveld, Llewellyn Wardle (2014) JAMA Pediatr: 168; 345-50 van Jaarsveld, Llewellyn, Johnson, Wardle (2011) Am J Clin Nutr; 94:1562-7
APPETITE IS HIGHLY HERITABLE IN INFANCY, SUGGESTING AN APPETITIVE PATHWAY FOR OBESITY GENES 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 MZ (N=716) DZ (N=1576) MZ (N=718) DZ (N=1582) Food Responsiveness Satiety Responsiveness Llewellyn, van Jaarsveld, Johnson, Carnell, Wardle (2010) Am J Clin Nutr: 91; 1172-1179
APPETITE IS HIGHLY HERITABLE IN INFANCY, SUGGESTING AN APPETITIVE PATHWAY FOR OBESITY GENES 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 h 2 =0.59 (0.52, 0.65) MZ (N=716) DZ (N=1576) h 2 =0.72 (0.65, 0.80) MZ (N=718) DZ (N=1582) Food Responsiveness Satiety Responsiveness Llewellyn, van Jaarsveld, Johnson, Carnell, Wardle (2010) Am J Clin Nutr: 91; 1172-1179
APPETITE IS HIGHLY HERITABLE IN BOTH INFANCY AND CHILDHOOD, SUPPORTING BST 1 0.9 h 2 =0.75 (0.52, 0.85) h 2 =0.63 (0.39, 0.81) 1 0.9 h 2 =0.59 (0.52, 0.65) h 2 =0.72 (0.65, 0.80) 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 MZ (N=1919) DZ (N=3478) MZ (N=1928) DZ (N=3478) 0 MZ (N=716) DZ (N=1576) MZ (N=718) DZ (N=1582) Food Responsiveness Satiety Responsiveness Food Responsiveness Satiety Responsiveness Carnell et al (2008) Int J Obes: 32; 1468-1473 Llewellyn et al (2010) Am J Clin Nutr: 91; 1172-1179
IMPLICATIONS Variation in human body weight has a strong genetic basis Variation in appetite also has a strong genetic basis Variation in early appetite drives early weight gain Inherited variation in appetite bestows differential susceptibility to obesity Establish if appetitive traits are amenable to change
ACKNOWLEDGEMENTS Prof Jane Wardle (Gemini PI) Prof Robert Plomin (TEDS PI) Prof Stephen O Rahilly Prof Sadaf Farooqi Dr Susan Carnell Dr Laura Johnson Dr Maciej Trzaskowski David Boniface Dr Ellen van Jaarsveld