10 - obesity genetics

Question 1

is obesity all caused by environmental factors

Answer 1

no

there is a genetic component to where you are on the BMI scale

Question 2

non-changeable risk factors for cardio-vascular disease

Answer 2

age
gender
- men store fat around organs (middle)

Question 3

obesity epidemic

Answer 3

massive increase in obesity
all caused by environment

average BMI increased from 20 (1950) to 27 (2012)

too rapid to be genetic

Question 4

evidence that obesity epidemic must be due to environment

Answer 4

native american indians
lifestyle changed dramatically over last 100 years
massive increase in prevalence of T2 diabetes
genes cannot change that quickly

Question 5

evidence that 50% of BMI variation is due to genetics

Answer 5

twin studies
much stronger correlations between BMIs of identical twins compared to non-identical
assuming their environments are the same

siblings that share more of their genomes (e.g. 60% compared to 40%) have more similar BMIs

Question 6

rare mutations causing disease

Answer 6

maturity onset diabetes of the young

Question 7

severe genetic defects causing obesity

Answer 7

loss of appetite control in children

e.g. prader-willi syndrome

Question 8

importance of leptin

Answer 8

hormone made by adipose cells

regulates energy balance by inhibiting hunger

acts on receptors of arcuate nucleus in hypothalamus

Question 9

importance of melanocortin 4 receptor

Answer 9

GPCR associated with inherited obesity

mutations of receptor causes severe obesity

shown by a large family with recessive inheritance of MC4 receptor

Question 10

absence of leptin or leptin receptor (hypothalamus)

Answer 10

lack of inhibitory effect on apetite increasing pathway

therefore always feel hungry

Question 11

prader willi syndrome

Answer 11

imprinting gene disorder

occurs when copy from father of chromosome 15 switched off
or if chromosome 15 from mum is switched on

weak muscles, learning difficulties, constant hunger –> leads to T2 diabetes

Question 12

evidence gained from GWAS studies

Answer 12

found 97 regions of the genome associated with BMI

mutations affecting appetite control mostly expressed in the brain

Question 13

result of overweight mothers on offspring

Answer 13

increases chances of neonates being larger for their gestational age

however mechanisms poorly understood

Question 14

maternal traits found to increase size of offspring

Answer 14

increased BMI
increased fasting glucose
increased systolic blood pressure

Question 15

mendelian randomisation

Answer 15

using genetic variation (of a known function) to examine causal effect of exposure on disease

Question 16

association between increased BMI and depression

Answer 16

no significant directionality

however stronger association between increased BMI and increased odds of depression (especially in women)

Question 17

macro-nutrients

Answer 17

proportion of calories consumed from different food groups

carbohydrates, proteins, fats

Question 18

macronutrients are a modifiable risk factor for…

Answer 18

CV disease
obesity
T2 diabetes

Question 19

genetic loci already known to be associate with macronutrients

Answer 19

FGF21

FTO

Question 20

genetic loci discovered in study to be associated with macronutrients

Answer 20

RARB

DRAM1

Question 21

FGF21

Answer 21

associated with increased consumption of carbohydrates and alcohol intake

Question 22

FTO

Answer 22

associated with obesity and high protein diets

Question 23

RARB

Answer 23

regulatory genetic variant associated with increased carbohydrates intake

Question 24

results from GWAS meta-analysis of macronutrients

Answer 24

food preference is affected by genetics
identified 4 genetic loci:
- FGF21
- FTO
- RARB
- DRAM1

Question 25

results of study looking at obesity and psoriasis

Answer 25

increased BMI causally increases risk of psoriasis
9% increase in psoriasis risk for every 1 kg/m2 increase in BMI

poor understanding of mechanistic relationships

used reverse MR analysis to determine directionality of association

Question 26

twin study looking at genetic influence on child adiposity

Answer 26

during increase in obesity epidemic

cohort split into monozygotic and dizygotic twins
in pair differences measured
BMI and waist circumference

both BMI and WC 77% heritable

environmental influence also important

Question 27

why are twins important for genetic studies

Answer 27

differences in phenotypes between monozygotic twin pairs and dizygotic pairs with same environment identify traits which are genetic

Question 28

monogenic

Answer 28

when mutation in a single gene is responsible for the disease caused

Question 29

results from study looking at monogenic inheritance of severe obesity

Answer 29

autosomal dominant mutations in MC4R are most common cause of severe obesity, main regulator of body weight –> no developmental delay

identified obesity syndromes associated with developmental delay

Question 30

examples of obesity syndromes associated with developmental delay

Answer 30

prader willi syndrome

bardet biedl syndrome

Question 31

symptoms and genetics of bardet biedl syndrome

Answer 31

autosomal recessive
can be tri-allelic

can cause obesity, infertility, polydactyly and cognitive impairment

Question 32

tri-allelic

Answer 32

3 different alleles at the same genetic locus

Question 33

are monogenic diseases rare

Answer 33

yes
individually each disease is rare
however collectively, monogenic diseases make up 10% of all children with severe obesity

Question 34

what binds to MC4R

Answer 34

α-melanocyte stimulating hormone (α-MSH)

Question 35

impact of MC4R on obesity

Answer 35

important for feeding behaviours
regulates metabolism –> how much energy is taken up by the body

MC4R mutations associated with inherited obesity

Question 36

homozygous for MC4R mutations

Answer 36

often loss of function
increased chance of obese phenotype

evidence from comparison of brothers with mutations (one heterozygous, one homozygous)

Question 37

effect of MC4R deficiency on plasma insulin concentration

Answer 37

MC4R deficiency causes increase in fasting plasma insulin concentration compared to obese controls without MC4R deficiency

Question 38

FGF21

Answer 38

fibroblast growth factor 21
liver-derived hormone
has effects on metabolic processes

Question 39

metabolic effects of FGF21

Answer 39

normalises blood glucose in diabetic animals
increases fatty acid oxidation
alleviates beta cell dysfunction
decreases body weight in diet-induced obese mice

Question 40

result of FGF21 study

Answer 40

FGF21 is a negative regulator of sweet consumption
levels rise after oral sucrose consumption
levels are 51% higher in those who dislike sweet foods