Introduction to the Genomics Era

Abdel Abdellaoui

dr_appie a.abdellaoui@amsterdamumc.nl
Where do similarities and
differences between living
organisms come from?

It took a while before we

had the answer.
350 BC

Pythagoras &
Aristotle:
Parents pass on
characteristics
to offspring
Pythagoras suggested that the
father supplies the essential
characteristics (“form”) and
the mother supplies the
material building blocks.

Aristotle thought children

were made from purified
blood (semen) and menstrual
blood.
The next important advances were
made in the 17th century.
• Scientists showed in animals that
“like breeds like” & that all female
organisms produced eggs
• Two Dutch scientists saw sperm cells
and claimed that there were little
human beings inside of sperm cells.
350 BC

Pythagoras &
Aristotle:
Parents pass on
characteristics
to offspring
 Darwin
publishes On
the Origin of
Species

350 BC

1859

Pythagoras &
Aristotle:
Parents pass on
characteristics
to offspring
 Theory of evolution: all species arose through the natural
selection of small, inherited variations that increase the
individual's ability to compete, survive, and reproduce.

The first phylogenetic Phylogenetic tree

tree as drawn by Darwin Modern drawing of based on genomic
phylogenetic tree clustering analysis
 Darwin
publishes On
the Origin of
Species

350 BC

1859

Pythagoras &
Aristotle:
Parents pass on
characteristics
to offspring
 Darwin
publishes On
the Origin of
Species

350 BC 1865

1859

Pythagoras & Mendel

Aristotle: discovers basic
Parents pass on laws
characteristics of inheritance
to offspring
Mendel’s laws of Mendelian Inheritance:
Mendel’s laws of Mendelian Inheritance:
• Law of segregation:
• One out of two alleles is passed down by
each parent
Mendel’s laws of Mendelian Inheritance:
• Law of segregation:
• One out of two alleles is passed down by
each parent

• Law of dominance:
• Some alleles are dominant, and some are
recessive. An organism with at least one
dominant allele will display the effect of
the dominant allele
Mendel’s laws of Mendelian Inheritance:
• Law of segregation:
• One out of two alleles is passed down by
each parent

• Law of dominance:
• Some alleles are dominant, and some are
recessive. An organism with at least one
dominant allele will display the effect of
the dominant allele

• Law of independent assortment:

• Genes for different traits are passed down
independently from each other
 Darwin
publishes On
the Origin of
Species

350 BC 1865

1859

Pythagoras & Mendel

Aristotle: discovers basic
Parents pass on laws
characteristics of inheritance
to offspring
 Darwin First twin
publishes On study, Francis
the Origin of Galton
Species

350 BC 1865

1859 1875

Pythagoras & Mendel

Aristotle: discovers basic
Parents pass on laws
characteristics of inheritance
to offspring
“There are twins of the same sex so alike in body and
mind that not even their own mothers can distinguish
them. Their features, voice, and expressions are similar;
they see things in the same light, and their ideas follow
the same laws of association.”

He used twins to study the power of the environment to change twins

(i.e., make initially similar twins different & initially different twins similar).

He did not compare identical and fraternal twins to estimate heritability.

 Darwin First twin
publishes On study, Francis
the Origin of Galton
Species

350 BC 1865

1859 1875

Pythagoras & Mendel

Aristotle: discovers basic
Parents pass on laws
characteristics of inheritance
to offspring
 Darwin First twin
publishes On study, Francis
the Origin of Galton
Species

350 BC 1865 1918

1859 1875

Pythagoras & Mendel Ronald Fisher:

Aristotle: discovers basic Mendelian
Parents pass on laws rules apply to
characteristics of inheritance continuous
to offspring traits
In the beginning of the 1900s,
controversy arose between:
• Mendelians: qualitative traits that
show Mendelian patterns of
inheritance
• Biometricians: quantitative traits
that are normally distributed
In the beginning of the 1900s,
controversy arose between:
• Mendelians: qualitative traits that
show Mendelian patterns of
inheritance
• Biometricians: quantitative traits
that are normally distributed

Ronald Fisher united the two camps

In the beginning of the 1900s,
controversy arose between:
• Mendelians: qualitative traits that
show Mendelian patterns of
inheritance
• Biometricians: quantitative traits
that are normally distributed

Ronald Fisher united the two camps

Complex Trait: trait with an (underlying) continuous dimension

that are influenced by many genes with small effects
 Darwin First twin
publishes On study, Francis
the Origin of Galton
Species

350 BC 1865 1918

1859 1875

Pythagoras & Mendel Ronald Fisher:

Aristotle: discovers basic Mendelian
Parents pass on laws rules apply to
characteristics of inheritance continuous
to offspring traits
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on
the Origin of Galton skin disorders
Species and IQ

350 BC 1865 1918

1859 1875 1920s

Pythagoras & Mendel Ronald Fisher:

Aristotle: discovers basic Mendelian
Parents pass on laws rules apply to
characteristics of inheritance continuous
to offspring traits
• The first studies in which monozygotic (MZ) and dizygotic (DZ) twins
were compared to estimate heritability were done in the late 1920s
on skin disorders and on IQ.
“First law of behavior genetics”:
All human behavioral traits are heritable.

Genetic influences
Shared environmental influences
Unique environmental influences
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on
the Origin of Galton skin disorders
Species and IQ

350 BC 1865 1918

1859 1875 1920s

Pythagoras & Mendel Ronald Fisher:

Aristotle: discovers basic Mendelian
Parents pass on laws rules apply to
characteristics of inheritance continuous
to offspring traits
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on
the Origin of Galton skin disorders
Species and IQ

350 BC 1865 1918 1953

1859 1875 1920s

Pythagoras & Mendel Ronald Fisher: Structure of

Aristotle: discovers basic Mendelian DNA (double
Parents pass on laws rules apply to helix)
characteristics of inheritance continuous discovered
to offspring traits
https://www.youtube.com/watch?v=y7hbOTltfio
Watson, Crick, and Franklin discovered the double helix, and thereby the
molecular basis of inheritance and evolution.

There are 20 amino-acids coded for in

three letter words called “codons”
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on
the Origin of Galton skin disorders
Species and IQ

350 BC 1865 1918 1953

1859 1875 1920s

Pythagoras & Mendel Ronald Fisher: Structure of

Aristotle: discovers basic Mendelian DNA (double
Parents pass on laws rules apply to helix)
characteristics of inheritance continuous discovered
to offspring traits
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953

1859 1875 1920s 1980s

Pythagoras & Mendel Ronald Fisher: Structure of

Aristotle: discovers basic Mendelian DNA (double
Parents pass on laws rules apply to helix)
characteristics of inheritance continuous discovered
to offspring traits
• Linkage study: locating disease genes by demonstrating co-segregation of
genetic markers and disease within families
• Linkage study: locating disease genes by demonstrating co-segregation of
genetic markers and disease within families
• Very suitable for large effects: genes were found for many single gene
disorders (Mendelian traits)
• Linkage study: locating disease genes by demonstrating co-segregation of
genetic markers and disease within families
• Very suitable for large effects: genes were found for many single gene
disorders (Mendelian traits)

Also worked to find genes for some complex

traits, but only those with very large effects:
• Diabetes (Insulin gene)
• Breast cancer (BRCA1 & BRCA2 genes)
• Alzheimer (APOE genes)
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1919 1953

1859 1875 1920s 1980s

Pythagoras & Mendel Ronald Fisher: Structure of

Aristotle: discovers basic Mendelian DNA (double
Parents pass on laws rules apply to helix)
characteristics of inheritance continuous discovered
to offspring traits
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953 2003

1859 1875 1920s 1980s

Pythagoras & Mendel Ronald Fisher: Structure of Human

Aristotle: discovers basic Mendelian DNA (double Genome
Parents pass on laws rules apply to helix) Project
characteristics of inheritance continuous discovered
to offspring traits
Human Genome Project
• Planning started in 1984, was launched
in 1990, and completed in 2003
• Goal: map all 3 billion nucleotides of
the human genome
• Costs: 3 billion dollars

“We are here to celebrate the completion of the first survey of the entire
human genome. Without a doubt, this is the most important, most
wondrous map ever produced by humankind.”
- President Bill Clinton, 26-06-2000, the White House
https://www.youtube.com/watch?v=AhsIF-cmoQQ
Next step:
Make haplotype maps
Next step:
Make haplotype maps by
genotyping/sequencing populations!

• In 2005, the first phase of the HapMap

project was published: 269 individuals
from 4 populations with several million
well-defined genetic variants
• In 2012, the first phase of 1000
Genomes project was released: 1,092
individuals from 14 populations
sequenced
 Darwin First twin First MZ vs DZ
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953 2003

1859 1875 1920s 1980s

Pythagoras & Mendel Ronald Fisher: Structure of Human

Aristotle: discovers basic Mendelian DNA (double Genome
Parents pass on laws rules apply to helix) Project
characteristics of inheritance continuous discovered
to offspring traits
 Darwin First twin First MZ vs DZ First GWAS
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953 2003

1859 1875 1920s 1980s 2005

Pythagoras & Mendel Ronald Fisher: Structure of Human

Aristotle: discovers basic Mendelian DNA (double Genome
Parents pass on laws rules apply to helix) Project
characteristics of inheritance continuous discovered
to offspring traits
 Candidate gene studies
• The serotonin transporter transports
serotonin from the synaptic cleft to
the presynaptic neuron
• Serotonin affects mood, sleep,
appetite, memory, and more
 Candidate gene studies
• Mono-amine oxidase (MAO-A):
an enzyme that degrades
noradrenaline, adrenaline,
serotonin, and dopamine.
• Candidate gene studies have not worked very well… We are not very good at
finding genes based on hypotheses 
• In a Genome-Wide Association Study (GWAS) we measure as many variants as
possible and test every single one! (hypothesis-free)
• Thanks to haplotype reference maps, we don’t need to sequence the entire
genome to measure all variation!
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 Published Genome-Wide Associations through 07/2012
Published GWA at p ≤ 5X10-8 for 18 trait categories

NHGRI GWA Catalog

www.genome.gov/GWAStudies
www.ebi.ac.uk/fgpt/gwas/
 Number of significant findings grows with increasing sample size!

Large studies possible thanks to large collaborative efforts (consortia).

 Darwin First twin First MZ vs DZ First GWAS
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953 2003

1859 1875 1920s 1980s 2005

Pythagoras & Mendel Ronald Fisher: Structure of Human

Aristotle: discovers basic Mendelian DNA (double Genome
Parents pass on laws rules apply to helix) Project
characteristics of inheritance continuous discovered
to offspring traits
 Darwin First twin First MZ vs DZ First GWAS
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953 2003 2009-2018

1859 1875 1920s 1980s 2005

Pythagoras & Mendel Ronald Fisher: Structure of Human Genes for

Aristotle: discovers basic Mendelian DNA (double Genome psychiatric and
Parents pass on laws rules apply to helix) Project behavioral
characteristics of inheritance continuous discovered traits
to offspring traits discovered
 Major Depressive Disorder
2013 - N ~18,000 2018 - N ~460,000

Loneliness
2018 - N ~475,000
 Educational Attainment

2016 - N ~320,000
2013 - N ~126,000

2018 - N ~1,100,000
Non-heterosexual behaviour
2018 - N ~493,000

Cannabis Use (Ever vs Never)

2018 - N ~ 185,000
 Schizophrenia

N ~50,000 N ~150,000
 Schizophrenia
2016

Influences “synaptic pruning” — the

elimination of connections between
neurons

N ~50,000 N ~150,000
Not all of the heritability is explained by the significant GWAS SNPs

Heritability
Not all of the heritability is explained by the significant GWAS SNPs

Heritability

Variance explained by significant SNPs

Not all of the heritability is explained by the significant GWAS SNPs

Heritability

SNP Heritability

Variance explained by significant SNPs

The non-significant SNPs have “real” signal in them. Why are
they not significant?
The non-significant SNPs have “real” signal in them. Why are
they not significant?

• They have very small effects

• We are extremely stringent in what we call “genome-wide”

significant due to a huge multiple testing burden
We are extremely stringent in what we call “genome-wide”
significant due to a huge multiple testing burden.

With an α of .05, a GWAS of 3,000,000 SNPs is expected to

give 150,000 (!) significant signals by chance.
Not all of the heritability is explained by the significant GWAS SNPs

Heritability

SNP Heritability Potential for polygenic scores!

Variance explained by significant SNPs

 With polygenic scores, we use all the signal from the GWAS
(including non-significant SNPs) to build a score that is predictive
of complex traits

1×-.02 + 2×.01 + 1×.002 + 0×.03 + 2×.025

Polygenic score:

AC GG CC TT .052
AT

Effect sizes from

βC=-.02 βG=.01 βA=.002 βG=.03 βT=.025
GWAS
Future of polygenic scores:
• As predictive power increases,
clinical utility will increase
• 23andMe just got FDA approval
to include polygenic score
predictions in their feedback
• Potential impact on genetic
make-up of population: partner
and offspring choice?
History of the Dutch Population Structure
History of the Dutch Population Structure
History of the Dutch Population Structure

1849 Today

Catholic Protestant Non-religious

 Darwin First twin First MZ vs DZ First GWAS
publishes On study, Francis twins study on Genome-wide
the Origin of Galton skin disorders linkage studies
Species and IQ

350 BC 1865 1918 1953 2003 2009-2018

1859 1875 1920s 1980s 2005

Pythagoras & Mendel Ronald Fisher: Structure of Human Genes for

Aristotle: discovers basic Mendelian DNA (double Genome psychiatric and
Parents pass on laws rules apply to helix) Project behavioral
characteristics of inheritance continuous discovered traits
to offspring traits discovered
 Darwin First twin First MZ vs DZ First GWAS UK Biobank
publishes On study, Francis twins study on Genome-wide releases
the Origin of Galton skin disorders linkage studies 500,000
Species and IQ individuals
genotyped for
the public

350 BC 1865 1918 1953 2003 2009-2018

1859 1875 1920s 1980s 2005

Pythagoras & Mendel Ronald Fisher: Structure of Human Genes for

Aristotle: discovers basic Mendelian DNA (double Genome psychiatric and
Parents pass on laws rules apply to helix) Project behavioral
characteristics of inheritance continuous discovered traits
to offspring traits discovered
 Large-scale datasets
 Several countries have started to realize the potential of
“population-scale” epidemiological studies and are investing in
them accordingly:
 The UK has invested in the large long-term biobank study UK Biobank,
where ~500,000 volunteers are genotyped
 Large-scale datasets
 Several countries have started to realize the potential of
“population-scale” epidemiological studies and are investing in
them accordingly:
 The UK has invested in the large long-term biobank study UK Biobank,
where ~500,000 volunteers are genotyped

Abdellaoui et al (2018). Genetic Consequences of Social

Stratification in Great Britain
 Large-scale datasets
 Several countries have started to realize the potential of
“population-scale” epidemiological studies and are investing in
them accordingly:
 The UK has invested in the large long-term biobank study UK Biobank,
where ~500,000 volunteers are genotyped

Educational Townsend
Attainment Index
Abdellaoui et al (2018). Genetic Consequences of Social
Polygenic Score Stratification in Great Britain
 Large-scale datasets
 Several countries have started to realize the potential of
“population-scale” epidemiological studies and are investing in
them accordingly:
 The UK has invested in the large long-term biobank study UK Biobank,
where ~500,000 volunteers are genotyped
 The biopharmaceutical company deCODE in Iceland has measured the
genomes of ~150,000 Icelanders (~half of their population)

Maps show how common certain risk-causing DNA mutations

are around Iceland.
 Large-scale datasets
 Several countries have started to realize the potential of
“population-scale” epidemiological studies and are investing in
them accordingly:
 The UK has invested in the large long-term biobank study UK Biobank,
where ~500,000 volunteers are genotyped
 The biopharmaceutical company deCODE in Iceland has measured the
genomes of ~150,000 Icelanders (~half of their population)
 The US based company 23andme has more 5 million customers
genotyped
 http://www.research.va.gov/mvp/
https://www.whitehouse.gov/precision-medicine
If the 20th century was the century
of physics, the 21st century will be
the century of biology.
- Craig Venter
Meanwhile, another revolution is taking place in genetics…

https://www.youtube.com/watch?v=jAhjPd4uNFY
 Thank you!

a.abdellaoui@amsterdamumc.nl dr_appie