TWINS AND GENETICS TWINS
Heritability: Twin Studies
Twin studies are often used to assess genetic effects on variation in a trait
Comparing MZ/DZ twins can give evidence for genetic and/or environmental influences
3
Understanding Genetic and Environmental Influences Using Twin Studies
Monozygotic Twins
100% genes
100% home environment
Understanding Genetic and Environmental Influences Using Twin Studies
Monozygotic Twins
100% genes
100% home environment
Dizygotic Twins
50% genes
100% home environment
Understanding Genetic and Environmental Influences Using Twin Studies
Monozygotic Twins
100% genes
100% home environment
Dizygotic Twins
50% genes
100% home environment
We are a combination of our genes and environment.
Do both twins show the same characteristic or trait? Trait
Concordance rate
Monozygotic
Dizygotic
Height
95%
52%
IQ
90%
60%
Determining the incidence of a disease in twins helps delineate whether there are genetic and environmental components
Both genetic and environmental factors important
Disease
Concordance
Identical (MZ)
Non‐identical (DZ)
Cleft lip and palate
38%
8%
Rheumatoid arthritis
34%
7%
Asthma
47%
24%
Coronary artery disease
19%
9%
Diabetes mellitus
56%
11%
MZ and DZ concordance rates
The contributions of genetic and environmental factors to human diseases
Haemophilia
Osteogenesis imperfecta
Duchenne muscular dystrophy
Peptic ulcer
Diabetes
Club foot
Pyloric stenosis
Dislocation of hip
GENETIC
Phenylketonuria
Galactosaemia
Rare
Genetics simple
Unifactorial
High recurrence rate
Tuberculosis
ENVIRONMENTAL
Spina bifida
Ischaemic heart disease
Ankylosing spondylitis
Scurvy
Common
Genetics complex
Multifactorial
Low recurrence rate
What are Polygenic and Multifactorial Trait?
Polygenic traits are controlled by two or more
genes
Multifactorial traits are polygenic with an
environmental component
Example: Height
The Genes are inherited in Mendelian fashion
Interaction of genes with environment produce
many different phenotypes
Height as a Multifactorial Trait
Typical Polygenic Trait in a Population
Bell curve
Most individuals are clustered at ~average
Few individuals at extremes of the phenotype
Variation in Height
Characteristics of Multifactorial Traits
• Several genes control trait
• Not inherited as dominant or recessive
• Genes controlling trait contribute a small amount to phenotype
• Environmental factors interact with genes to produce phenotype
• Many phenotypic differences in trait
How can the probability of recurrence be determined for multifactorial disorders? • The recurrence risk for multifactorial disorders has to be determined through family studies
• Observe the number of affected siblings in many families (empiric risk)
Proband
Families with one child with multifactorial condition
Siblings of proband
50 brothers and sisters Proband
Families with one child with multifactoria
l condition
Siblings of proband
50 brothers and sisters 2 affected with multifactorial condition
Proband
Siblings of proband
2/50 affected with multifactorial condition
Families with one child with multifactoria
l condition
Therefore probability of recurrence = 1/25 (4%)
Multifactorial: cleftlip/palatet
• Examples include some cases of cleft lip and palate; neural tube defects; diabetes and hypertension
• Caused by a combination of genetic predisposition and environmental influences
• Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X‐linked inheritance patterns Family studies of the incidence of cleft lip (± cleft palate)
Anomaly Risk to sibs % 5.7 4.2 2.5 Bilateral cleft lip and palate Unilateral cleft lip and palate Unilateral cleft lip alone The more severe the manifestation of a multifactorial condition, the greater the probability of recurrence Some multifactorial conditions have an unequal sex ratio
Condition Pyloric stenosis Sex ratio (males to females) 5 to 1 Hirschprung disease 3 to 1 Congenital dislocation of hip 1 to 6 Talipes 2 to 1 Rheumatoid arthritis 1 to 3 Peptic ulcer 2 to 1 For some conditions there must be a different threshold for males and females
Frequency of pyloric stenosis in relatives
Relationship Frequency % Increase on general population risk for same sex Male relatives of a male patient Female relatives of a male patient Male relatives of a female patient Female relatives of a female patient 5 x10 2 x20 17 x35 1 x70 Pyloric stenosis occurs more commonly in boys than in girls; for a female to be affected with pyloric stenosis, she must have a particularly strong genetic susceptibility Multifactorial inheritance:
Factors increasing probability of recurrence in a particular family
•
Close relationship to proband
•
High heritability of disorder (more than 1family member affected)
•
Proband of more rarely affected sex
•
Severe or early onset disease
•
Multiple family members affected
All these suggest that the family has a higher liability to the disorder – genes of higher effect or more adverse environmental influences
Multifactorial inheritance:
Recurrence risk decreases rapidly in more remotely related individuals How evidence is gathered for genetic factors in complex diseases
•
Familial risks
(what is the incidence of a disorder in relatives compared with the incidence in the general population?)
•
Twin studies
(what is the incidence in monozygotic compared with dizygotic twins?)
•
Adoption studies
(what is the incidence in adopted children of the disorders which their parent had?) •
Population and Migration studies
(what is the incidence in people from a particular ancestry group when they move to a different geographical area?)
Evidence from these types of studies can estimate the heritability of a condition ‐ the proportion of the aetiology ascribed to genetic factors rather than environmental factors
In multifactorial disorders, there is a threshold, above which a person will develop the multifactorial disorder
No.of individuals in population
Threshold
Liability
Multifactorial disorders – practice points
Common conditions
“Environmental” influences act with a genetic predisposition
Multiple genes with individually small risks often implicated One organ system affected
Recurrence risks:
‐ “empiric figures”
‐ obtained from population studies
‐ use in population from No.of affected
which obtained
+ environment
Threshold
individuals
Liability (genetic and environmental factors)
Major effort to identify common disease susceptibility genes underway
Risk factors for coronary artery disease
Uncontrollable (but identifiable)
Potentially controllable or treatable
Family history (genetics)
Age
Male sex
Fatty diet
Hypertension
Smoking
High serum cholesterol
Low serum HDL
High serum LDL
Stress
Insufficient exercise
Obesity
Diabetes
Common diseases
• Congenital malformations
Cleft lip/palate
Congenital hip dislocation Congenital heart defects
Neural tube defects
Pyloric stenosis
Talipes
• Adult onset disorders
Diabetes mellitus
Epilepsy
Glaucoma
Hypertension
Ischaemic heart disease
Manic depression
Schizophrenia
Victor A. McKusick
Inheritance of monogenic and complex
(multifactorial) disorders.
In monogenic diseases, mutations in a single gene are both
necessary and sufficient to produce the clinical phenotype and
to cause the disease. The impact of the gene on genetic risk for
the disease is the same in all families.
In complex disorders with multiple causes,
variations in a number of genes encoding different
proteins result in a genetic predisposition to a
clinical phenotype. Pedigrees reveal no Mendelian
inheritance pattern, and gene mutations are often
neither sufficient nor necessary to explain the
disease phenotype. Environment and life-style are
major contributors to the pathogenesis of complex
diseases.
However, between families the impact of these
same genes might be totally different. In one
family, a rare gene C (Family 3) might have a
large impact on genetic predisposition to a
disease. However, because of its rarity in the
general population, the overall population effect of
this gene would be small. Some genes that
predispose individuals to disease might have
minuscule effects in some families (gene D,
Family 3).
Is Intelligence a Multifactorial Trait?
• Head size was used to determine intelligence
• Early 20th century, psychological rather than physical methods
• Intelligence quotient (IQ) assumes that intelligence is a biological property
• Concordance in MZ twins raised together and apart indicates genetic and environmental factors
Quantitative Trait Loci (QTLs) • Use information from Human Genome Project
• Associated with reading disability (developmental dyslexia)
• Genes on chromosomes 6, 15, and 4 for cognitive ability
• Accumulated results indicate intelligence is polygenic and multifactorial trait
IQ and the Bell Curve
Human Genome and SNPs
• Now that the human genome is (mostly) sequenced, attention turning to the evaluation of variation
• Alterations in DNA involving a single base pair are called single nucleotide polymorphisms, or
SNPs
• Map of ~1.4 million SNPs (Feb 2001)
• It is estimated that ~60,000 SNPs occur within exons; 85% of exons within 5 kb of nearest SNP
Disease‐Marker Association
• A marker locus is associated with a disease if the distribution of genotypes at the marker locus in disease‐affected individuals differs from the distribution in the general population
• A specific allele may be positively associated (over‐represented in affecteds) or negatively
associated (under‐represented)
Examples: Alzheimer’s • Alzheimer’s disease and ApoE
E4 present
E4 absent
Patients
58
33
Controls
16
55
The E4 allele appears to be positively associated with Alzheimer’s disease: Odds Ratio = (58/16)/(33/55) = 6
VOLUME 43 | NUMBER 10 | OCTOBER 2011 , page 1006
Nature Genetics
Figure 1 Regional association plots of the eight SNPs at seven loci showing
genome-wide significant association (P < 5 × 10−8) with pulse pressure (PP)
and/or mean arterial pressure (MAP). (a–h) Shown is the statistical
significance of each SNP on the –log10 scale as a function of chromosome
position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel
SNP at each locus is shown in blue; the correlations (r2) of each of the
surrounding SNPs to the sentinel SNP are shown in the colors indicated in the
key. The fine-scale recombination rate is shown in blue. Gene positions are
indicated at the bottom.
Association is not a specifically genetic phenomenon.
It is simply a statistical statement about the co‐occurence of alleles or phenotypes .
Allele A is associated with disease D if people who have D also have A significantly more often (or maybe less often) than would be predicted from the individual frequencies of D and A in the population.
For example, HLA DR4 is found in 36% of the general UK population but in 78% of people with rheumatoid arthritis
Association has many different explanations not all of them are genetic:
>> direct cause: if you have allele A you are susceptible to disease D
To be a carrier of allele A is not necessary nor sufficient to develop D, but it increases the likelihood
>> natural selection: people who have disease D might be more likely to survive and have children if they also have allele A
>> population stratification: the general population contains several sub‐groups, and allele A is more frequent in one of them. HLA‐A1 is associated to the ability to eat with chopsticks in San Francisco HLA A1 is more frequent in Chinese, who are a large sub group in San Francisco.
Comparison of ‘identity by state’ and ‘identity by descent’.
Kok H S et al. Hum. Reprod. Update 2005;11:483-493
© The Author 2005. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oupjournals.org
Examples of ‘identity by descent’ (IBD).
Kok H S et al. Hum. Reprod. Update 2005;11:483-493
© The Author 2005. Published by Oxford University Press on behalf of the European Society of
Human Reproduction and Embryology. All rights reserved. For Permissions, please email:
journals.permissions@oupjournals.org
Affected sib pair analysis
