Genetics in Neuroscience
Table of Contents
Week 1, From Heritability to Functional Experiments....................................................................................... 2
Inherited variation .............................................................................................................................................. 5
If a trait is heritable, how are the causal genetic variants transmitted? →inheritance ..................................... 7
Discovering genes for complex traits with technologies ................................................................................... 11
Many implicated genes→ how to biologically interpret GWAS results ............................................................ 13
Designing functional follow-up experiments .................................................................................................... 13
Week 2, Genetic variation and genome-wide association (GWAS) .................................................................. 15
What does “genetics in neuroscience” bring to mind? ..................................................................................... 15
Genetic variation .............................................................................................................................................. 16
Genome-wide association studies .................................................................................................................... 21
Data collection ............................................................................................................................................. 23
Genotyping .................................................................................................................................................. 25
GWAS Quality control .................................................................................................................................. 28
GWAS- Imputation ....................................................................................................................................... 30
Association testing ....................................................................................................................................... 31
Meta-Analysis .............................................................................................................................................. 32
Replication ................................................................................................................................................... 32
Post-GWAS analysis ..................................................................................................................................... 33
Interpreting GWAS ....................................................................................................................................... 34
Week 3, Interpreting GWAS and biological annotation ................................................................................... 35
How do we go from genetic variant associations (GWAS) to mechanistic disease insight ............................... 36
How do we prioritize causal, functional variants from these intergenic small-effect GWAS hits? ................... 41
Week 4, Genetics Architecture of Traits and Diseases ..................................................................................... 55
Genetic Architecture of Traits and Diseases ..................................................................................................... 55
Week 4, Genetic risk prediction consumer DNA testing, the ‘gay GWAS’ ........................................................ 65
Polygenic Risk Prediction .................................................................................................................................. 65
Consumer DNA testing ..................................................................................................................................... 69
The ‘gay’ GWAS ................................................................................................................................................ 71
Week 5, Aggregating and interpreting genetic associations ............................................................................ 73
Gene-based analysis ......................................................................................................................................... 75
Interpreting GWAS risk loci ............................................................................................................................... 83
,Week 1, From Heritability to Functional Experiments
Learning aims:
1. Understand heritability and how it is estimated
2. See the connections between heritability studies, gene identification, and functional
experiments
3. Understand the processes underlying (Mendelian) inheritance
4. Identify the main challenges in genetic research of neuropsychiatric traits
The field of human genetics is a baby field and developing fast
• Rapid changes in past decades
- new technologies
- novel methods
- large scale collaborations
- novel disease insights
• Very brief overview of the field and link between genetics and neuroscience: from twin
studies to induced pluripotent stem cells
Currently, there are millions of data on genetics of individuals instead of just twin studies
GWAS: which genes are responsible for a trait or disease
- We now can extract meaning of genes
Why are we all different? But also what makes family members alike?
- Genetics!
- Genetics shapes the risks and likelihoods of diseases and predispositions
Most challenging in genetics: nature vs. nurture
- Are people different because of genes or due to their environment
- Competing theories which sometimes also can complement each other
Why are nature and nurture so difficult to disentangle?
- They influence each other (interactions and correlations)
- You can’t influence the environment or take it away
- Most challenging: usually people who share genetics also share their environment
Solution: twin studies
- Comparing monozygotic to dizygotic twins
Monozygotic (MZ) twins Dizygotic (DZ) twins (regular siblings)
• share 100% of their genes (G) • share on average 50% of their genes (G)
• 100% of their common/family • 100% of their common/family
environment (C) environment (C)
• 0% of unique environment (E) • 0% of unique environment (E)
• rMZ = 1*G + 1*C • rDZ = 0.5*G + 1*C
,Simple math to estimate the contribution of genes vs. environment:
G = 2(rMZ - rDZ) (measure of heritability estimate)
E = 1 – rMZ (unique environment)
C = 1 - G – E (common environment)
100% heritable? Similarity in MZ twins twice as high as in DZ twins:
rMZ = 1.0, rDZ = 0.5
Correlation in phenotype, heritability estimates:
100% heritable gene?
- Monozygotic twins have a correlation of 1.0 in phenotype
- Dizygotic twins have a correlation of 0.5 in phenotype
100% common (family) environment? Similarity in MZ twins equals similarity in DZ twins:
rMZ = rDZ = 1.0
100% unique (individual) environment? No similarity between twins:
rMZ = rDZ = 0
Heritability
• Proportion of trait variance between individuals that is attributable to genetic variance
between individuals
- The part of trait variance that is due to genes; not due to environment
- We talk about population prediction not individual prediction
• Causes genetically related individuals to correlate on a trait (phenotype)
Trait variance: total amount of variability in the population on a certain trait
- Two random people of the population→ normal distribution
o Height of 1 does not influence the height of the other
- When you look at two family members, they will be closer in the distribution
o Because they are more similar → genetic variance?
If two monozygotic twins differ in height, this difference in height must be due to the
environment as they share exactly the same DNA.
Trait= anything we can measure
, Reflection: What does heritability mean?
Is heritability destiny? Think about what it means for a phenotype (trait/disease) to be 100%
heritable
- You could die before getting the disease, this would mean it is not heritable as the
disease is not expressed
- We talk about the entire population not about the individual
- Something that might be very heritable in one population might be not in another
population
When a phenotype is 0% heritable, does it mean that no genes have any influence on it?
- There can still be an interaction between genetics and environment?
- Language is not heritable, however, how fast you learn a language may is
List a phenotype that you think is
- 0% heritable→ language and religious affiliation
- 50% heritable→ alcohol and drug use disorders; Alzheimer’s
- 100% heritable (never totally 100%)→ Physical traits (hair colour, eye colour shape
ear etc.)
Those traits that are more influenced by the environment: lower heritability
Left: One population where there are the same conditions: same environment. However
there is difference in height: this would be due to the genetics.
The difference between the left and right condition, who both have 100% heritability, is due
to environmental differences.
Table of Contents
Week 1, From Heritability to Functional Experiments....................................................................................... 2
Inherited variation .............................................................................................................................................. 5
If a trait is heritable, how are the causal genetic variants transmitted? →inheritance ..................................... 7
Discovering genes for complex traits with technologies ................................................................................... 11
Many implicated genes→ how to biologically interpret GWAS results ............................................................ 13
Designing functional follow-up experiments .................................................................................................... 13
Week 2, Genetic variation and genome-wide association (GWAS) .................................................................. 15
What does “genetics in neuroscience” bring to mind? ..................................................................................... 15
Genetic variation .............................................................................................................................................. 16
Genome-wide association studies .................................................................................................................... 21
Data collection ............................................................................................................................................. 23
Genotyping .................................................................................................................................................. 25
GWAS Quality control .................................................................................................................................. 28
GWAS- Imputation ....................................................................................................................................... 30
Association testing ....................................................................................................................................... 31
Meta-Analysis .............................................................................................................................................. 32
Replication ................................................................................................................................................... 32
Post-GWAS analysis ..................................................................................................................................... 33
Interpreting GWAS ....................................................................................................................................... 34
Week 3, Interpreting GWAS and biological annotation ................................................................................... 35
How do we go from genetic variant associations (GWAS) to mechanistic disease insight ............................... 36
How do we prioritize causal, functional variants from these intergenic small-effect GWAS hits? ................... 41
Week 4, Genetics Architecture of Traits and Diseases ..................................................................................... 55
Genetic Architecture of Traits and Diseases ..................................................................................................... 55
Week 4, Genetic risk prediction consumer DNA testing, the ‘gay GWAS’ ........................................................ 65
Polygenic Risk Prediction .................................................................................................................................. 65
Consumer DNA testing ..................................................................................................................................... 69
The ‘gay’ GWAS ................................................................................................................................................ 71
Week 5, Aggregating and interpreting genetic associations ............................................................................ 73
Gene-based analysis ......................................................................................................................................... 75
Interpreting GWAS risk loci ............................................................................................................................... 83
,Week 1, From Heritability to Functional Experiments
Learning aims:
1. Understand heritability and how it is estimated
2. See the connections between heritability studies, gene identification, and functional
experiments
3. Understand the processes underlying (Mendelian) inheritance
4. Identify the main challenges in genetic research of neuropsychiatric traits
The field of human genetics is a baby field and developing fast
• Rapid changes in past decades
- new technologies
- novel methods
- large scale collaborations
- novel disease insights
• Very brief overview of the field and link between genetics and neuroscience: from twin
studies to induced pluripotent stem cells
Currently, there are millions of data on genetics of individuals instead of just twin studies
GWAS: which genes are responsible for a trait or disease
- We now can extract meaning of genes
Why are we all different? But also what makes family members alike?
- Genetics!
- Genetics shapes the risks and likelihoods of diseases and predispositions
Most challenging in genetics: nature vs. nurture
- Are people different because of genes or due to their environment
- Competing theories which sometimes also can complement each other
Why are nature and nurture so difficult to disentangle?
- They influence each other (interactions and correlations)
- You can’t influence the environment or take it away
- Most challenging: usually people who share genetics also share their environment
Solution: twin studies
- Comparing monozygotic to dizygotic twins
Monozygotic (MZ) twins Dizygotic (DZ) twins (regular siblings)
• share 100% of their genes (G) • share on average 50% of their genes (G)
• 100% of their common/family • 100% of their common/family
environment (C) environment (C)
• 0% of unique environment (E) • 0% of unique environment (E)
• rMZ = 1*G + 1*C • rDZ = 0.5*G + 1*C
,Simple math to estimate the contribution of genes vs. environment:
G = 2(rMZ - rDZ) (measure of heritability estimate)
E = 1 – rMZ (unique environment)
C = 1 - G – E (common environment)
100% heritable? Similarity in MZ twins twice as high as in DZ twins:
rMZ = 1.0, rDZ = 0.5
Correlation in phenotype, heritability estimates:
100% heritable gene?
- Monozygotic twins have a correlation of 1.0 in phenotype
- Dizygotic twins have a correlation of 0.5 in phenotype
100% common (family) environment? Similarity in MZ twins equals similarity in DZ twins:
rMZ = rDZ = 1.0
100% unique (individual) environment? No similarity between twins:
rMZ = rDZ = 0
Heritability
• Proportion of trait variance between individuals that is attributable to genetic variance
between individuals
- The part of trait variance that is due to genes; not due to environment
- We talk about population prediction not individual prediction
• Causes genetically related individuals to correlate on a trait (phenotype)
Trait variance: total amount of variability in the population on a certain trait
- Two random people of the population→ normal distribution
o Height of 1 does not influence the height of the other
- When you look at two family members, they will be closer in the distribution
o Because they are more similar → genetic variance?
If two monozygotic twins differ in height, this difference in height must be due to the
environment as they share exactly the same DNA.
Trait= anything we can measure
, Reflection: What does heritability mean?
Is heritability destiny? Think about what it means for a phenotype (trait/disease) to be 100%
heritable
- You could die before getting the disease, this would mean it is not heritable as the
disease is not expressed
- We talk about the entire population not about the individual
- Something that might be very heritable in one population might be not in another
population
When a phenotype is 0% heritable, does it mean that no genes have any influence on it?
- There can still be an interaction between genetics and environment?
- Language is not heritable, however, how fast you learn a language may is
List a phenotype that you think is
- 0% heritable→ language and religious affiliation
- 50% heritable→ alcohol and drug use disorders; Alzheimer’s
- 100% heritable (never totally 100%)→ Physical traits (hair colour, eye colour shape
ear etc.)
Those traits that are more influenced by the environment: lower heritability
Left: One population where there are the same conditions: same environment. However
there is difference in height: this would be due to the genetics.
The difference between the left and right condition, who both have 100% heritability, is due
to environmental differences.
