Genetics in neuroscience
Contents
Lecture 1: Introduction to genetics.........................................................................................................2
Lecture 2: Genetic variation and genome-wide association (GWAS)......................................................8
Lecture 3: Interpreting GWAS and biological annotation......................................................................18
Lecture 4: Genetic architecture of traits and diseases..........................................................................28
Guest lecture: Genetic risk prediction, consumer DNA testing, the ‘gay GWAS’...................................33
Lecture 5: Aggregating and interpreting genetic associations..............................................................36
Paper 1: Basic genetics.........................................................................................................................43
Paper 2: Genome-wide association studies..........................................................................................44
Paper 3: Genome-scale neurogenetics: methodology and meaning....................................................45
Paper 4: Benefits and Limitations of Genome-Wide Association Studies.............................................46
Paper 5: Genome-Wide Association Studies.........................................................................................48
Paper 6: Data quality control in genetic case-control association studies............................................49
Paper 7: 10 Years of GWAS Discovery: Biology, Function, and Translation............................................51
Paper 8: Functional mapping and annotation of genetic associations with FUMA...............................52
Paper 9: Emerging Methods and Resources for Biological Interrogation of Neuropsychiatric
PolygenicSignal.....................................................................................................................................54
Paper 10: Pitfalls of predicting complex traits from SNPs.....................................................................55
Paper 11: Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior
..............................................................................................................................................................57
Paper 12: Analysis of shared heritability in common disorders of the brain.........................................58
Paper 13: Unraveling the genetic architecture of major depressive disorder: merits and pitfalls of the
approaches used in genome-wide association studies.........................................................................60
Paper 14: The statistical properties of gene-set analysis......................................................................61
Paper 15: An historical framework for psychiatric nosology.................................................................63
,Lecture 1: Introduction to genetics
Learning goals:
Understand heritability and how it is estimated
See the connections between heritability studies, gene identification, and functional
experiments
Understand the processes underlying (Mendelian) inheritance
Identify the main challenges in genetic research of neuropsychiatric traits
Rapid changes are made in human genetics in the past decades, such as new technologies, novel
methods, large scale collaborations and novel disease insights.
Challenges in Determining Genetic vs. Environmental Influence
Determining the influence of genetics (nature) vs. environment (nurture) is complex.
Twin studies help identify the extent of each influence by comparing:
o Monozygotic (MZ) twins:
Share 100% of their genes (G).
Share 100% of their common/family environment (C).
Share 0% of unique environment (E).
Formula for MZ similarity
rMZ = 1*G + 1*C
o Dizygotic (DZ) twins:
Share 50% of their genes (G) on average.
Share 100% of their common/family environment (C).
Share 0% of unique environment (E).
Formula for DZ similarity
rDZ = 0.5*G + 1*C
Key Observations in Twin Studies
Genetic influence only: MZ twins would be identical for a trait, while DZ twins would be 50%
similar.
Environmental influence only: One MZ twin might exhibit a trait while the other does not.
Correlation measurement:
o 1.0 indicates 100% correlation or similarity.
Estimating Genetic, Common, and Unique Environmental Contributions
Formulas for estimating contributions of genetics vs. environment:
o Genetic influence (G): G = 2(rMZ - rDZ)
o Unique environment (E): E = 1 – rMZ
o Common environment (C): C = 1 - G - E
Interpreting Results
100% heritable: If similarity in MZ twins is twice as high as in DZ twins.
o Example: rMZ = 1.0, rDZ = 0.5
100% common environment: If MZ and DZ twins show equal similarity.
o Example: rMZ = rDZ = 1.0
, 100% unique environment: No similarity between twins.
o Example: rMZ = rDZ = 0
Heritability
Heritability: The proportion of trait variance between individuals that is due to genetic variance.
Explains why genetically related individuals show similar traits (phenotype).
Suggests that variations in genes underlie trait differences between individuals
Key Questions:
Does heritability mean destiny?
o High heritability does not guarantee an outcome, as it is an expression of probability.
What does it mean if a phenotype is 100% heritable?
o It suggests all variance in the trait is due to genetic differences in the population.
If a phenotype is 0% heritable, does it mean genes have no influence?
o No, it just means environmental factors are the main cause of variation in that
specific context.
Factors Influencing Heritability
Trait Variance:
o Normally distributed across populations, with genetic variance among individuals.
o Family members often cluster closer together within the distribution.
Heritability is Context- and Population-Specific:
o Heritability estimates vary depending on the environment and population studied.
Genetic Influence on Traits
General Estimate: Many traits show ~50% heritability, though this varies widely.
Alleles and Disease Risk:
o Each allele can contribute a slightly higher risk of disease.
In this case it follows an additive model of genetic influence, meaning traits
are not strictly dominant or recessive.
o An disease allele can also be either dominant or recessive
Twin studies
Studies conducted between 1900 and 2012 in twins
, Collected sample size (N) and correlation (r) for both monozygotic (MZ) and dizygotic (DZ)
Twins
Calculated
o h² (heritability) – genetic contribution.
o C² (common/family environment) – shared family influence.
o e² (unique environment) – individual environmental impact.
Trait Classification:
o Used standardized categories:
Actual trait (classified by ICF or ICD10).
General trait category.
Main trait domain.
Traits Studied:
o Mostly easily measured traits (e.g., weight, height, blood pressure).
o Also included more complex traits, like neurological disorders.
Key Findings from 50 Years of Twin Studies:
o All traits are heritable to some extent (average heritability around 50%).
o Influence of C² (common/family environment) is relatively small for most traits.
o Majority of traits fit a model where genetic variance is additive (individual alleles
contribute cumulatively to trait variance).
Genetic Basis of Heritable Traits:
If a trait is heritable:
o Examine DNA to find causal genetic variants.
Human genome details:
o 23 chromosomes with 3 billion base pairs (fully sequenced).
o Approximately 24,000 genes coding for polypeptide chains.
Genetic Similarities Across Species:
Humans and mice share 87.5% of DNA.
Humans and chimpanzees share 99% of DNA.
Two individual humans share 99.9% of DNA
The 0.1% base pair sites that differ...
o …are the genetic causes of phenotypic differences between unrelated individuals
o …explain (part of) why genetically similar individuals are more alike phenotypically
Types of Genetic Variations:
Occur within genes (protein coding, regulatory regions, exonic, intronic – 5% of genome).
Occur outside genes (regulatory regions or unknown functions – 95% of genome).
Effects of Genetic Variations:
Harmless: Alters phenotype without negative impact.
Harmful: Linked to diseases (e.g., diabetes, cancer, Huntington's disease).
Helpful: Provides evolutionary advantages.
Latent: Effects depend on other genes or environmental factors.
Silent: No observable impact.
Types of Genetic Disorders:
Contents
Lecture 1: Introduction to genetics.........................................................................................................2
Lecture 2: Genetic variation and genome-wide association (GWAS)......................................................8
Lecture 3: Interpreting GWAS and biological annotation......................................................................18
Lecture 4: Genetic architecture of traits and diseases..........................................................................28
Guest lecture: Genetic risk prediction, consumer DNA testing, the ‘gay GWAS’...................................33
Lecture 5: Aggregating and interpreting genetic associations..............................................................36
Paper 1: Basic genetics.........................................................................................................................43
Paper 2: Genome-wide association studies..........................................................................................44
Paper 3: Genome-scale neurogenetics: methodology and meaning....................................................45
Paper 4: Benefits and Limitations of Genome-Wide Association Studies.............................................46
Paper 5: Genome-Wide Association Studies.........................................................................................48
Paper 6: Data quality control in genetic case-control association studies............................................49
Paper 7: 10 Years of GWAS Discovery: Biology, Function, and Translation............................................51
Paper 8: Functional mapping and annotation of genetic associations with FUMA...............................52
Paper 9: Emerging Methods and Resources for Biological Interrogation of Neuropsychiatric
PolygenicSignal.....................................................................................................................................54
Paper 10: Pitfalls of predicting complex traits from SNPs.....................................................................55
Paper 11: Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior
..............................................................................................................................................................57
Paper 12: Analysis of shared heritability in common disorders of the brain.........................................58
Paper 13: Unraveling the genetic architecture of major depressive disorder: merits and pitfalls of the
approaches used in genome-wide association studies.........................................................................60
Paper 14: The statistical properties of gene-set analysis......................................................................61
Paper 15: An historical framework for psychiatric nosology.................................................................63
,Lecture 1: Introduction to genetics
Learning goals:
Understand heritability and how it is estimated
See the connections between heritability studies, gene identification, and functional
experiments
Understand the processes underlying (Mendelian) inheritance
Identify the main challenges in genetic research of neuropsychiatric traits
Rapid changes are made in human genetics in the past decades, such as new technologies, novel
methods, large scale collaborations and novel disease insights.
Challenges in Determining Genetic vs. Environmental Influence
Determining the influence of genetics (nature) vs. environment (nurture) is complex.
Twin studies help identify the extent of each influence by comparing:
o Monozygotic (MZ) twins:
Share 100% of their genes (G).
Share 100% of their common/family environment (C).
Share 0% of unique environment (E).
Formula for MZ similarity
rMZ = 1*G + 1*C
o Dizygotic (DZ) twins:
Share 50% of their genes (G) on average.
Share 100% of their common/family environment (C).
Share 0% of unique environment (E).
Formula for DZ similarity
rDZ = 0.5*G + 1*C
Key Observations in Twin Studies
Genetic influence only: MZ twins would be identical for a trait, while DZ twins would be 50%
similar.
Environmental influence only: One MZ twin might exhibit a trait while the other does not.
Correlation measurement:
o 1.0 indicates 100% correlation or similarity.
Estimating Genetic, Common, and Unique Environmental Contributions
Formulas for estimating contributions of genetics vs. environment:
o Genetic influence (G): G = 2(rMZ - rDZ)
o Unique environment (E): E = 1 – rMZ
o Common environment (C): C = 1 - G - E
Interpreting Results
100% heritable: If similarity in MZ twins is twice as high as in DZ twins.
o Example: rMZ = 1.0, rDZ = 0.5
100% common environment: If MZ and DZ twins show equal similarity.
o Example: rMZ = rDZ = 1.0
, 100% unique environment: No similarity between twins.
o Example: rMZ = rDZ = 0
Heritability
Heritability: The proportion of trait variance between individuals that is due to genetic variance.
Explains why genetically related individuals show similar traits (phenotype).
Suggests that variations in genes underlie trait differences between individuals
Key Questions:
Does heritability mean destiny?
o High heritability does not guarantee an outcome, as it is an expression of probability.
What does it mean if a phenotype is 100% heritable?
o It suggests all variance in the trait is due to genetic differences in the population.
If a phenotype is 0% heritable, does it mean genes have no influence?
o No, it just means environmental factors are the main cause of variation in that
specific context.
Factors Influencing Heritability
Trait Variance:
o Normally distributed across populations, with genetic variance among individuals.
o Family members often cluster closer together within the distribution.
Heritability is Context- and Population-Specific:
o Heritability estimates vary depending on the environment and population studied.
Genetic Influence on Traits
General Estimate: Many traits show ~50% heritability, though this varies widely.
Alleles and Disease Risk:
o Each allele can contribute a slightly higher risk of disease.
In this case it follows an additive model of genetic influence, meaning traits
are not strictly dominant or recessive.
o An disease allele can also be either dominant or recessive
Twin studies
Studies conducted between 1900 and 2012 in twins
, Collected sample size (N) and correlation (r) for both monozygotic (MZ) and dizygotic (DZ)
Twins
Calculated
o h² (heritability) – genetic contribution.
o C² (common/family environment) – shared family influence.
o e² (unique environment) – individual environmental impact.
Trait Classification:
o Used standardized categories:
Actual trait (classified by ICF or ICD10).
General trait category.
Main trait domain.
Traits Studied:
o Mostly easily measured traits (e.g., weight, height, blood pressure).
o Also included more complex traits, like neurological disorders.
Key Findings from 50 Years of Twin Studies:
o All traits are heritable to some extent (average heritability around 50%).
o Influence of C² (common/family environment) is relatively small for most traits.
o Majority of traits fit a model where genetic variance is additive (individual alleles
contribute cumulatively to trait variance).
Genetic Basis of Heritable Traits:
If a trait is heritable:
o Examine DNA to find causal genetic variants.
Human genome details:
o 23 chromosomes with 3 billion base pairs (fully sequenced).
o Approximately 24,000 genes coding for polypeptide chains.
Genetic Similarities Across Species:
Humans and mice share 87.5% of DNA.
Humans and chimpanzees share 99% of DNA.
Two individual humans share 99.9% of DNA
The 0.1% base pair sites that differ...
o …are the genetic causes of phenotypic differences between unrelated individuals
o …explain (part of) why genetically similar individuals are more alike phenotypically
Types of Genetic Variations:
Occur within genes (protein coding, regulatory regions, exonic, intronic – 5% of genome).
Occur outside genes (regulatory regions or unknown functions – 95% of genome).
Effects of Genetic Variations:
Harmless: Alters phenotype without negative impact.
Harmful: Linked to diseases (e.g., diabetes, cancer, Huntington's disease).
Helpful: Provides evolutionary advantages.
Latent: Effects depend on other genes or environmental factors.
Silent: No observable impact.
Types of Genetic Disorders:
