Introduction lecture
Vanishing boundaries between neurodevelopmental disorders
1. genetic underpinnings
2. molecular pathways
3. cellular processes
4. brain regions
5. behavior & phenotype
Genetic causes of disease
- chromosomal defects: molecular cytogenetics
- Monogenic disorders: mendelian inheritanc (autosomal dominant (de novo),
autosomal recessive, x-linked)
- other mechanisms: imprinting, mitochondrial inheritance, anticipation, multifactorical
inheritance
- Intellectual disability is often mendelian (only due to genetic factors) → most
psychiatric disorders (ASD, schizo, …) are rather non-mendelian (also influenced by
environmental factors)
- very common variations (polymorphisms) do not have a very strong effect on the
phenotype
- rare alleles stay rare due to selection (e.g if you have an intellectual disability the
chance of getting children is low so these genes will not be given to the next
generation, when you have a deadly genomic disease you will not have children
because you don’t live long enough)
- SNPs are the most common type of variation
,Karyotyping: the process by which a karyotype is prepared from photographs of
chromosomes, in order to determine the chromosome complement of an individual, including
the number of chromosomes and any abnormalities → done in microarray studies
→ microarrays are used for:
- mapping Mendelian disorders (linkage analysis)
- genomic disorders (copy number variation (CNVs))
- mapping risk alleles in complex disorders (GWAS)
- expression studies (transcriptomics)
→ microarrays do not need to be used nowadays we can also do sequencing or
bionanomapping
22q11 deletion syndrome: Velo-cardio-facial syndrome (found with CNV genomic mapping)
→ clinical characteristics: physical (facial, fingers), congenital heart defect, hypoplasia of
thymus, cleft palate, velopharyngeal insufficiency, parathyroid dysfunction with
hypocalcemia, neuro-psychiatric problems ( schizophrenia (25%), bipolar disorder,
depression, anxiety) → responsible for 0.5-1% of all schizophrenia cases (in this case,
schizophrenia becomes a mendelian disease)
SNP: single nucleotide polymorphism → most studied genetic variation in human disease,
easy to genotype, current analysis methodology designed to use these variants, flexible and
adaptable for multiple types of genetic mapping studies
GWAS: genome-wide association studies → linkage analysis: most loci segregate
independently (linkage equilibrium), but if loci are physically close, you get linkage
disequilibrium
,Linkage disequilibrium (LD): co-occurrence of at least two SNPs in a determined physical
region on the genome in a non-random way → the longer the piece of chromosome that is
being exchanged, the higher the probability of recombination
GWAS
- case-control for genetic association
- manhattan plots
x-axis: SNPs ordered by chromosome and position on each chromosome
y-axis: probability (p-value) of the level of enrichment in case versus control
→ manhattan plots show places on the chromosome (no specific gene) of many
SNPs in cases where not many SNPs are found in controls → genetic risk-factors
- in the Manhattan plot of significant associations in schizophrenia you don’t see a
peak in 22q11 because it is a very rare deletion that can occur on every chromosome
→ not strictly connected to a certain SNP profile (random deletion)
- the same gene can lead to different phenotypes due to allele-specific phenotypes,
genetic background effects, environmental contributions, wrong annotation of
variance/causality
Allele-specific phenotype/expression: unbalanced expression from the two parental alleles in
a tissue of a diploid organism → one gene can lead to different phenotypes (due to different
kinds of variation wihtin that gene) → vanishing boundaries
- the 108 loci that have been found with GWAS studies to be a risk factor for
schizophrenia only explain about 4% of the underlying genetic variation → it is
estimated that there are about 8000SNPs that independently contribute to
schizophrenia and which together will explain about 50% of the genetic
, predisposition → we are all carriers of some of those risk genes, the additional risk for
each SNP is very limited, very large cohorts are needed to identify those SNPs (not
all patients in test cohorts are multifactorial)
- ID is not always Mendelian, psychiatric disorders are not always multifactorial (Id not
always monogenic, ASD not always multifactorial)
de novo mutation: genetic alteration that is present for the first time in one family member as
a result of a variant (or mutation) in a germ cell (only in the child, not in the parents) → might
explain a certain genetic disease, but not necessarily
→ every person has about 1 de novo mutation
Next-generation sequencing
→ used to identify 1 causative variant (study design: child parent trios)
- Illumina Novaseq
- Ion Torrent
- HiSeq
- Pacific biosciences
- Oxford Nanopore
- huge overlap in variance of the same genes in multiple psychiatric disorders → this is
also why you often see comorbidities → it can also be that a mutation on the same
allele can lead to a different protein and with that to a different phenotype and thus a
different disorder
Intellectual disability (or ID): a term used when a person has certain limitations in cognitive
functioning and skills, including communication, social and self-care skills. These limitations
can cause a child to develop and learn more slowly or differently than a typically developing
child.
Vanishing boundaries between neurodevelopmental disorders
1. genetic underpinnings
2. molecular pathways
3. cellular processes
4. brain regions
5. behavior & phenotype
Genetic causes of disease
- chromosomal defects: molecular cytogenetics
- Monogenic disorders: mendelian inheritanc (autosomal dominant (de novo),
autosomal recessive, x-linked)
- other mechanisms: imprinting, mitochondrial inheritance, anticipation, multifactorical
inheritance
- Intellectual disability is often mendelian (only due to genetic factors) → most
psychiatric disorders (ASD, schizo, …) are rather non-mendelian (also influenced by
environmental factors)
- very common variations (polymorphisms) do not have a very strong effect on the
phenotype
- rare alleles stay rare due to selection (e.g if you have an intellectual disability the
chance of getting children is low so these genes will not be given to the next
generation, when you have a deadly genomic disease you will not have children
because you don’t live long enough)
- SNPs are the most common type of variation
,Karyotyping: the process by which a karyotype is prepared from photographs of
chromosomes, in order to determine the chromosome complement of an individual, including
the number of chromosomes and any abnormalities → done in microarray studies
→ microarrays are used for:
- mapping Mendelian disorders (linkage analysis)
- genomic disorders (copy number variation (CNVs))
- mapping risk alleles in complex disorders (GWAS)
- expression studies (transcriptomics)
→ microarrays do not need to be used nowadays we can also do sequencing or
bionanomapping
22q11 deletion syndrome: Velo-cardio-facial syndrome (found with CNV genomic mapping)
→ clinical characteristics: physical (facial, fingers), congenital heart defect, hypoplasia of
thymus, cleft palate, velopharyngeal insufficiency, parathyroid dysfunction with
hypocalcemia, neuro-psychiatric problems ( schizophrenia (25%), bipolar disorder,
depression, anxiety) → responsible for 0.5-1% of all schizophrenia cases (in this case,
schizophrenia becomes a mendelian disease)
SNP: single nucleotide polymorphism → most studied genetic variation in human disease,
easy to genotype, current analysis methodology designed to use these variants, flexible and
adaptable for multiple types of genetic mapping studies
GWAS: genome-wide association studies → linkage analysis: most loci segregate
independently (linkage equilibrium), but if loci are physically close, you get linkage
disequilibrium
,Linkage disequilibrium (LD): co-occurrence of at least two SNPs in a determined physical
region on the genome in a non-random way → the longer the piece of chromosome that is
being exchanged, the higher the probability of recombination
GWAS
- case-control for genetic association
- manhattan plots
x-axis: SNPs ordered by chromosome and position on each chromosome
y-axis: probability (p-value) of the level of enrichment in case versus control
→ manhattan plots show places on the chromosome (no specific gene) of many
SNPs in cases where not many SNPs are found in controls → genetic risk-factors
- in the Manhattan plot of significant associations in schizophrenia you don’t see a
peak in 22q11 because it is a very rare deletion that can occur on every chromosome
→ not strictly connected to a certain SNP profile (random deletion)
- the same gene can lead to different phenotypes due to allele-specific phenotypes,
genetic background effects, environmental contributions, wrong annotation of
variance/causality
Allele-specific phenotype/expression: unbalanced expression from the two parental alleles in
a tissue of a diploid organism → one gene can lead to different phenotypes (due to different
kinds of variation wihtin that gene) → vanishing boundaries
- the 108 loci that have been found with GWAS studies to be a risk factor for
schizophrenia only explain about 4% of the underlying genetic variation → it is
estimated that there are about 8000SNPs that independently contribute to
schizophrenia and which together will explain about 50% of the genetic
, predisposition → we are all carriers of some of those risk genes, the additional risk for
each SNP is very limited, very large cohorts are needed to identify those SNPs (not
all patients in test cohorts are multifactorial)
- ID is not always Mendelian, psychiatric disorders are not always multifactorial (Id not
always monogenic, ASD not always multifactorial)
de novo mutation: genetic alteration that is present for the first time in one family member as
a result of a variant (or mutation) in a germ cell (only in the child, not in the parents) → might
explain a certain genetic disease, but not necessarily
→ every person has about 1 de novo mutation
Next-generation sequencing
→ used to identify 1 causative variant (study design: child parent trios)
- Illumina Novaseq
- Ion Torrent
- HiSeq
- Pacific biosciences
- Oxford Nanopore
- huge overlap in variance of the same genes in multiple psychiatric disorders → this is
also why you often see comorbidities → it can also be that a mutation on the same
allele can lead to a different protein and with that to a different phenotype and thus a
different disorder
Intellectual disability (or ID): a term used when a person has certain limitations in cognitive
functioning and skills, including communication, social and self-care skills. These limitations
can cause a child to develop and learn more slowly or differently than a typically developing
child.
