GENETICS IN PSYCHIATRY

NIRAN OKEWOLE,mbbs,msc,fwacp,fmcpsy
Senior Consultant Psychiatrist
Child and Adolescent Unit
Neuropsychiatric Hospital Aro
 Background History

• Antiquity
• Plant and animal breeding
• Humans???
Jean B. Lamarck (1744-1829)

• 1809: Jean Lamarck

publishes Philosophie
Zoologique, in which
he discusses the
inheritance of
acquired xtics. Use
and disuse theory.
Charles Darwin (1809-1882)

• 1859: Charles Darwin

publishes The Origin
of Species, which
describes the theory of
evolution by natural
selection. This theory
requires heredity to
work.
Gregor Mendel (1822-1884)

• 1866: Gregor Mendel

publishes Experiments
in Plant Hybridization,
which lays out the
basic theory of
genetics. It is widely
ignored until 1900.
chromosomes
 Mendel’s Laws

• First Law (Law of segregation): During gamete formation,

the alleles for each gene segregate from each other so that
each gamete carries only one allele for each gene.
• Second Law (Law of independent assortment):Genes for
different traits can segregate independently during the
formation of gametes.
• Third Law (Law of dominance): Some alleles are
dominant while others are recessive; an organism with at
least one dominant allele will display the effect of the
dominant allele.
 patterns of inheritance

• Autosomal recessive
• Autosomal dominant
• X-linked recessive
• X-linked dominant
• Codominant
• Mitochondrial
 Autosomal recessive

• The disease appears

in male and female
children of
unaffected parents.
• e.g., several inborn
errors of
metabolism

9
 Autosomal dominant

• Affected males and

females appear in each
generation of the
pedigree.
• Affected mothers and
fathers transmit the
phenotype to both sons
and daughters.
• e.g., Huntington disease.

10
 X-linked recessive

• Many more males than

females show the disorder.
• All the daughters of an
affected male are
“carriers”.
• None of the sons of an
affected male show the
disorder or are carriers.
• e.g., hemophilia

11
 X-linked dominant

• Affected males pass the

disorder to all daughters
but to none of their sons.
• Affected heterozygous
females married to
unaffected males pass the
condition to half their sons
and daughters
• e.g. fragile X syndrome

12
 Codominant inheritance
• Two different versions
(alleles) of a gene can be
expressed, and each
version makes a slightly
different protein
• Both alleles influence the
genetic trait or determine
the characteristics of the
genetic condition.
• E.g. ABO locus

13
 Mitochondrial inheritance
• This type of inheritance
applies to genes in
mitochondrial DNA
• Mitochondrial disorders
can appear in every
generation of a family and
can affect both males and
females, but fathers do
not pass mitochondrial
traits to their children.
• E.g. Leber's hereditary
optic neuropathy (LHON)

14
20th Century
20th Century
 20th Century

• 1900: rediscovery of Mendel’s work by Robert

Correns, Hugo de Vries, and Erich von Tschermak
.
• 1902: Archibald Garrod discovers that
alkaptonuria, a human disease, has a genetic basis.
• 1904: Gregory Bateson discovers linkage between
genes. Also coins the word “genetics”.
• 1918: R. A. Fisher begins the study of quantitative
genetics by partitioning phenotypic variance into a
genetic and an environmental component.
 20th Century

• Thomas Morgan (1866-1945): Located genes at

chromosomes and developed modern genetics through
experiments on Drosophila—fruit flies
• 1926: Hermann J. Muller shows that X-rays induce
mutations.
• 1944: Oswald Avery, Colin MacLeod and Maclyn McCarty
show that DNA can transform bacteria, demonstrating that
DNA is the hereditary material.
• Erwin Chargaff (1905-2002): Purine: pyrimidine ratio
• Erwin Schrodinger (1887-1961): What is Life?
The double helix
The double helix
 Post-Double Helix
• 1966: Marshall Nirenberg solves the genetic
code, showing that 3 DNA bases code for one
amino acid.
• Ed Southern: Southern Blot
• Barbara McClintock: The Nobel Prize in
Physiology or Medicine 1983 "for her
discovery of mobile genetic elements."
• Kary Mullis: PCR
• 2001: Sequence of the entire human genome is
announced.
BASIC STRUCTURE OF DNA

• Complementarity: bps
• Antiparallel (5’ to 3’)
• Each nucleotide of
DNA contains:
– Deoxyribose sugar
– Phosphate backbone
– Nitrogen base (either
purine: A or G; or
pyrimidine: C or T)
Nucleotide structure of RNA

• Each nucleotide of
RNA contains:
– Ribose
– Phosphate
– Nitrogen base (either
A, G, C, U*)

*contains Uracil
instead of Thymine
 BASIC CONCEPTS

• The Genetic Code

• The Central Dogma
• Transcription and Translation
 Structure of the human genome
• Coding region: ‘Exons’
• ‘Introns’: not exactly ‘junk’
• Primary structure: base sequence
• Secondary structure: base pairing/double helix
• Tertiary structure: the locations of the atoms in three-
dimensional space, taking into consideration geometrical
and steric constraints. [Handedness – right or left; length
of the helix turn; number of base pairs per turn; difference
in size between the major and minor grooves]
• Quaternary structure: higher-level organization of nucleic
acids in chromatin and histones.
 Gene regulation
Gene activity and expression (the process by
which proteins are made) is regulated by
• inherited DNA and RNA,
• non inherited mechanisms (epigenetics),
• endogenous biological factors such as
hormones,
• environmental factors operating externally to
the individual organism (e.g. toxins,
psychosocial stress).
 Traditional techniques: family study
• Family studies allow us to determine whether a disorder aggregates in
families by examining the rate of disorder in the relatives of affected
individuals (probands) and comparing this with the rate of disorder in
the general population or in a control group.
• Alternatively we can compare the frequency of disorder in the
relatives of probands with the frequency among relatives of a control
group of normal individuals or those with another disorder.
• Methods: family history and direct interview.
• Ascertainment
• Age correction: the Slater-Stromgen adaption of Weinberg’s shorter
method is the most straightforward. The MR of the disorder can be
estimated as the number of affecteds (A) divided by the bezugsziffer,
BZ(based on age of risk).
 Traditional techniques: twin study
• For dichotomous characteristics (e.g. affected with a
disorder and unaffected), twin similarity is expressed as
concordance rates.
• A pairwise concordance rate is estimated as the number of
twin pairs who both have the disorder divided by the total
number of pairs.
• However, where there has been systematic ascertainment,
for example a twin register, it is preferable to report a
probandwise concordance rate which is calculated as the
number of affected twins divided by the total number of
cotwins.
• Equal environments assumption (limitation)
Traditional techniques: adoption study
Adoption studies provide another means of teasing apart the effects of genes
and environment. The basic method of the adoption study lies in comparing
the rates of disorder in biological relatives and adoptive relatives. There are
three main types of adoption study.
• The adoptee study: Here the rate of disorder in the adopted-away
offspring of affected individuals is compared with the rate of disorder in
control adoptees whose biological parents are unaffected.
• The adoptee’s family study: In this design, the rate of disorder in the
biological relatives of affected adoptees is compared with that among the
adopted relatives.
• The cross-fostering study: This allows us to examine gene-environment
interaction by comparing the rate of disorder in adoptees who have
unaffected biological parents and affected adoptive parents with the rate of
disorder in adoptees who have affected biological parents and unaffected
adoptive parents.
 Quantitative methods
• Path analysis
• Model fitting
• Quantitative trail locus, QTL: a locus (section of DNA)
which correlates with variation of a quantitative trait in
the phenotype of a population of organisms. QTLs are
mapped by identifying which molecular markers (such as
SNPs or AFLPs) correlate with an observed trait. This is
often an early step in identifying and sequencing the
actual genes that cause the trait variation.
 Techniques in molecular genetics
• Restriction enzyme: or restriction endonuclease is an
enzyme that cleaves DNA into fragments at or near
specific recognition sites within the molecule known
as restriction sites.
• Restriction fragment length polymorphisms: Refers to a
difference between samples of homologous DNA
molecules from differing locations of
restriction enzyme sites, and to a related laboratory
technique by which these segments can be illustrated.
In RFLP analysis, the DNA sample is broken into pieces
(digested) by restriction enzymes and the
resulting restriction fragments are separated according to
their lengths by gel electrophoresis.
 Techniques in molecular genetics
• Molecular cloning: process of amplifying DNA fragments containing
whole genes, but it can also be used to amplify any DNA sequence
such as promoters, non-coding sequences and randomly fragmented
DNA.
• Steps: fragmentation - breaking apart a strand of DNA; ligation -
gluing together pieces of DNA in a desired sequence; transfection –
inserting the newly formed pieces of DNA into cells;
screening/selection – selecting out the cells that were successfully
transfected with the new DNA
• Recombinant DNA: are DNA molecules formed by laboratory
methods of genetic recombination (such as molecular cloning) to bring
together genetic material from multiple sources, creating sequences
that would not otherwise be found in the genome.
 Techniques in molecular genetics
• Gene tracking: Gene tracking A method for determining
the inheritance of a particular gene in a family. It is used in
the diagnosis of genetic diseases, such as cystic fibrosis
and Huntington's chorea.
Restriction fragment length polymorphisms (RFLPs)
situated in or near the locus of interest are identified using
gene probes, and suitable marker RFLPs selected. These
can then be traced through members of the family and used
to detect the presence or absence of the disease locus
prenatally in future at-risk pregnancies.
• Direct gene analysis: direct study of DNA from fetal
tissue. Reported in hemoglobinopathies with chorionic
villus sampling.
 Techniques in molecular genetics:
linkage
• In linkage studies, rather than just studying the
segregation of a disease in families, the co-
segregation of the disease and a set of genetic
markers is investigated.
• The aims are, first, to detect linkage, indicated by the
disorder and the marker co-occurring more often
than would be expected by chance (i.e. not showing
Mendelian independent assortment),
• second, to estimate the distance between a linked
marker and the gene conferring susceptibility to the
disorder.
 Techniques in molecular genetics:
linkage
• The recombination fraction, θ, is the number of
recombinants divided by total number of offspring.
• For two loci that are very widely separated on the same
chromosome (and all pairs of loci carried on to two different
chromosomes) independent assortment occurs and θ = 0.5
• When the two loci are close together dependent assortment
may be observed indicated by a recombination fraction of
less than a half.
• The size of the recombination fraction depends on the
physical distance between the two loci and (within certain
limits) is proportional to it, so that for loci that are very close
together recombination rarely occurs and θ tends to zero.
 Techniques in molecular genetics:
linkage
• The standard method of carrying out linkage analysis in
humans is the lod score approach devised by Morton.
• The lod score is so called because it is the common log of
the odds that θ has a certain value θ′; rather than a value of
0.5
• i.e. lod = log10probability(θ = θ′)/probability(θ = 0.5)
• By convention, a lod of 3 or more is accepted as indicating
that linkage has been detected, while a lod of −2 or less
indicates that linkage can be excluded at that particular
value of θ.
• A lod of 3 corresponds to odds on linkage of 1000:1 and to
a nominal P value of 0.0001.
 Techniques in molecular genetics:
• linkage
Genetic distances estimated by linkage studies are measured in
centimorgans (cM) with 1 cM the equivalent of a recombination
fraction of 0.01.
• With reasonable sample sizes major gene effects can be confidently
detected over distances of around 10 to 15 cM.
• A whole genome search can be carried out using 200 to 300
polymorphic markers, provided they are approximately evenly
spaced.
• A polymorphism can be defined as a gene or sequence of DNA that
occurs in two or more common forms.
• Classically, ‘common’ means an allele frequency of at least 1 per
cent.
• Sometimes combinations of allelic variants across different markers
(haplotypes) are analysed in gene mapping studies.
 Techniques in molecular genetics:
association
• A sample of cases affected by a disorder (or subjects who
have scores higher than a given threshold on a quantitative
measure) is compared with controls who do not have the
disorder (or subject whose scores are near average).
• The frequency of alleles at the marker locus is then
compared in the two groups. The significance of the
difference can then be compared in the usual way for
contingency table analysis using a χ2 test (or Fisher’s
exact test if expected frequencies are small).
• Relative risk is used as a measure of strength of
association, or odds ratio if the disorder is uncommon.
 Techniques in molecular genetics:
association
Mechanisms of allelic association:
• Linkage disequilibrium (Alleles at different loci that
are inherited together more frequently or less
frequently than expected by their individual
frequencies are said to show linkage disequilibrium.)
• A polymorphism within a gene itself has a functional
effect which results in susceptibility to a disease.
• Population stratification (the presence of a systematic
difference in allele frequencies between subpopulations
in a population, possibly due to different ancestry)
 Techniques in molecular genetics:
association
• Old approach: candidate genes.
• Functional candidate gene studies concentrate on
polymorphisms in or near genes that encode for proteins
that are likely to be involved in the disorder.
• Positional candidate gene studies involve selecting
genes that are in regions implicated by linkage.
• For example, a study of Scottish families with
translocations involving a region on chromosome 1 and
schizophrenia and bipolar disorder led to identification
of a susceptibility gene DISC1 for schizophrenia.
 Disorders: chromosomes
• Karyotyping, microarrays.
• Abnormalities of the number of chromosomes result in
aneuploidy.
• Deletion of part or an entire chromosome is termed a monosomy
(or haploinsufficiency);
• an extra copy of either part of or an entire chromosome is called
trisomy.
• A general term to describe either loss or excess of chromosomal
material is aneusomy.
• Most chromosomal abnormalities involve small regions of
aneusomy and consequently are known as segmental aneusomy
syndromes or contiguous gene syndromes.
 Disorders: mutations
• Changes in a single base pair of the coding sequence of the
gene may alter the function of the protein (missense
mutations),
• May result in premature termination of the protein product
(non-sense mutations)
• Or may create or destroy a splice site.
• In addition, deletions (of a single base pair or many
megabases of DNA) and insertions (again of any size)
disrupt transcription and translation of a gene.
• Deletions or insertions that do not affect a multiple of three
bases alter the way that the message is translated and are
known as frame-shift mutations.
 Disorders: case example
Genetic causes of intellectual disability
Chromosomal disorders
• Trisomies : Down’s syndrome, Edward’s syndrome, Patau’s syndrome
• Other aneuploidies : Turner’s syndrome (XO), Klinefelter’s syndrome (XXY)
• X-linked: Fragile X syndrome, Coffin–Lowry syndrome
Copy number variation
• Angelman syndrome (some cases),
• velocardiofacial syndrome, cri du chat
Single gene (Mendelian) disorders
• Autosomal dominant: Neurofibromatosis, tuberous sclerosis
• Autosomal recessive: Phenylketonuria, Tay–Sachs disease, Hurler’s syndrome
• X-linked: Rett syndrome
Mitochondrial disorders
Complex (non-Mendelian) disorders
 Disorders: triple repeats
Disease Repeat unit Gene Normal rpt Expanded rpt Mechanism
• Fragile X syndrome FRAXA (CGC)n FMRP 6–60 >200 Loss of function
• Fragile XE syndrome FRAXE (CCG)n FMR2 4–39 200–900 Loss of function
• Friedrich ataxia FRDA (GAA)n Frataxin 6–32 >200 Loss of function
• Myotonic dystrophy type 1 (CTG)n DMPK 5–37 50–10 000 RNA-mediated
• Myotonic dystrophy type 2 (CCTG)n ZNF9 10–26 >75 RNA-mediated
• Fragile X–associated tremor ataxia
• syndrome FXTAS (CGG)n FMR1 6–60 60–200 RNA-mediated
• Huntington disease HD (CAG)n Huntingtin 6–34 36–121 Polyglutamine expansion
• Spinocerebellar ataxia SCA1 (CAG)n Ataxin1 6–44b 39–82 Polyglutamine expansion
• Spinocerebellar ataxia SCA2 (CAG)n Ataxin2 15–24 32–200 Polyglutamine expansion
• Spinocerebellar ataxia SCA3 (CAG)n Ataxin3 13–36 61–84 Polyglutamine expansion
• Spinocerebellar ataxia SCA6 (CAG)n CACNA1A 4–19 10–33 Polyglutamine expansion
• Spinocerebellar ataxia SCA7 (CAG)n Ataxin7 4–35 37–306 Polyglutamine expansion
• Spinocerebellar ataxia SCA17 (CAG)n TBP 25–42 47–63 Polyglutamine expansion
• Spinobulbar muscular atrophy(CAG)n Androgen receptor 9–36 38–62 Polyglutamine expansion
• Spinocerebellar ataxia SCA8 (CTG)n SCA8 16–34 >74 Unknown
• Spinocerebellar ataxia SCA10 (ATTCT)n 10–20 500–4500 Unknown
• Spinocerebellar ataxia SCA12 (CAG)n PPP2R2B 7–45 55–78 Unknown
• Huntington disease-like 2 HDL2(CTG)n Junctophilin 7–28 66–78 Unknown
 anticipation
• Anticipation is a situation where disorders
show a progressively earlier onset and greater
severity with subsequent generations.
• It is now known to be explained by heritable
unstable nucleotide repeat sequences.
• Huntington’s chorea and fragile X syndrome
are examples of disorders caused by heritable
unstable repeats.
 Disorders: imprinting
• Imprinting is an epigenetic phenomenon that causes genes
to be expressed in a parent-of-origin-specific manner.
• Genomic imprinting is an inheritance process independent
of the classical Mendelian inheritance. It is an epigenetic
process that involves DNA methylation and
histone methylation without altering the genetic sequence.
• These epigenetic marks are established ("imprinted") in
the germline (sperm or egg cells) of the parents and are
maintained through mitotic cell divisions in the
somatic cells of an organism.
• Appropriate imprinting of certain genes is important for
normal development.
 Disorders: imprinting
• A number of diseases can be attributed to a failure to establish, maintain,
or recognize methylation.
• Rett syndrome is a progressive neurodevelopmental disorder that occurs
almost exclusively in females, with an incidence of between 1/10 000 and
1/15 000 live births.
• Most females with Rett syndrome are usually heterozygous for a de novo
mutation in methyl-CpG-binding protein MeCP2, a protein that induces
the recruitment of protein complexes involved in histone modifications
and chromatin remodelling.
• Prader–Willi syndrome and Angelman syndrome are both caused by
loss of function of imprinted genes on the proximal long arm of human
chromosome 15.
• Prader–Willi syndrome occurs if the paternal chromosome 15 is missing,
Angelman syndrome if the maternal. In a few per cent of patients the
disorder is due to aberrant imprinting and gene silencing.
 Psychiatric Disorders
• Mostly non-Mendelian
• Polygenic and Multifactorial
• Epigenetic Mechanisms
 Penetrance and expressivity
• Penetrance is defined as the probability of manifesting
the disorder given a particular genotype.
• For Mendelian disorders this is always 1 or 0, but
irregular patterns of inheritance may occur because of
incomplete penetrance where the probability of
manifesting the disorder is greater than 0 but <1.
• Expressivity: quantifies variation in a non-binary
phenotype across individuals carrying a particular
genotype. It is equal to the proportion of individual
carriers of a genotype for a trait who show the trait to a
specifiable extent.
 Components of phenotypic variation
The total variation in an observed trait (phenotype
vp) at the simplest level (ignoring non-additive
effects) can be partitioned into
• a proportion due to genetic influences (vg),
• a component explained by shared
environmental factors (vc),
• and a remainder accounted by non-shared
environmental factors which includes error (ve):
vp = vg + vc + ve
 Heritability
• The relative influence of genetic factors is expressed as
heritability
• When defined as the proportion of the total phenotypic
variance attributable to additive genetic variance, is
known as narrow-sense heritability:
hn2 = va/vp. Va being additive gen var.
• Heritability is also sometimes used to describe the
proportion of variance explained by the total genetic
variance (additive and non-additive genetic variance)
and it is then known as broad-sense heritability:
hb2 = va/vg.
 Despite diagnostic challenges, psychiatric diseases are among the
most heritable entities

Gottesman 1991
Cowan, Kopnisky, Hyman 2002 Sullivan, Daly, O’Donovan 2012
 Genome Wide Association Study
• Made possible by the HGP (2001).
• International Haplotype Map (HapMap) project, 1000Genomes,
etc.
• This involves a systematic search through the entire genome with
the aim of detecting linkage disequilibrium or direct association.
• This method has a particular attraction in the study of polygenic
disorders in that it should be capable of detecting genes of small
effect.
• Very high throughput genetic analysis involves hydridizing DNA
into many thousands of oligonucleotides on microarrays and allows
a very large number of biallelic single nucleotide polymorphisms
(SNPs) to be tested very rapidly and at comparatively low cost.
 Scz 2009;
2601 cases, 3345 controls
 Scz 2016;
60995 cases, 102860 controls
155 genome wide significant sites
 Gene–environment interaction
• Gene–environment interplay represents another important
form of non-additive genetic contribution to complex
phenotypes.
• The term gene–environment interaction (G × E) refers to
individual genetic differences in response to specific
environmental factors.
• In the presence of gene–environment interaction, individuals
who are at genetic risk of a disorder do not manifest the
condition unless they are exposed to a specific environmental
risk factor.
• Gene–environment interaction also means that not all those
exposed to an environmental risk factor will show disorder.
 Gene–environment correlation
• Gene–environment correlation arises when a person’s
genotype is correlated with the environment that they are
exposed to.
• For example, sociable parents not only endow their
children with genes but also provide an environment that
encourages greater sociability in their children (passive
gene–environment correlation).
• Positive gene–environment correlation would result where
a sociable child actively seeks out more situations where
socializing occurs (active gene–environment correlation) or
where he or she evokes friendly responses in others
(evocative gene–environment correlation).
Epigenetic mechanisms
 Prenatal identification
Prenatal screening tests: These tests can tell the chances that
a fetus has an aneuploidy and a few additional disorders.
• Carrier screening: done on (intending) parents. Blood or
tissue samples. Preimplantation GD.
• Ultrasound for nuchal translucency (1st trim), anomaly
scan (2nd trim). 2nd Trim: quad test (AFP, estriol and beta-
hcG plus inhibin A. The latter for trisomies.)
Prenatal diagnostic tests: These tests can tell whether a fetus
actually has certain disorders. These tests are done
on cells from the fetus or placenta obtained via
amniocentesis or chorionic villus sampling (CVS).
• Karyotyping, FISH, microarrays, direct gene testing.
 Genetic counseling
Genetic counselling is the process of advising individuals
and families affected by or at risk of genetic disorders to help
them understand and adapt to the medical, psychological and
familial implications of genetic contributions to disease. The
process integrates:
• Interpretation of family and medical histories to assess the
chance of disease occurrence or recurrence
• Education about inheritance, testing, management,
prevention, resources
• Counselling to promote informed choices and adaptation
to the risk or condition.
 Clinical Bioinformatics
• Bioinformatics: combines biology, computer
science and statistics for analysis of biological
data
• Clinical Bioinformatics: application to medical
understanding, diagnosis and therapeutics.
 The organization of clinical genetic
services, DNA banks.
• Location: teaching hospitals, specialist hospitals. Possibly
referral centre.
• Personnel: physicians (clinical and lab), lab scientists,
nurses, social workers, computer scientists and statisticians
• Functions: diagnosis, counselling, therapeutics and
research
• Space: ad hoc or purpose built
• Resources: hardware and consumables
• Funding: local or grants
• Collaboration is key.
 REFERENCES
• Oxford Textbook of Psychiatry
• Shorter Oxford Textbook of Psychiatry
• http://www.longwood.edu/staff/buckalewdw/Genetics.ppt
• http://www.cs.technion.ac.il/~anna_bi/cs236633/tutorials/Tutorial01.ppt
• https://
eclass.uoa.gr/modules/document/file.php/MATH268/Genetics/Lect_3/Sess
ion%201%20Overview.ppt
• http://www.kaniascience.com/uploads/Intro_to_Genetics__2003_.ppt
• http://
faperta.ugm.ac.id/newbie/download/pak_tar/genetics/2014-historyofgeneti
cs.ppt
• http://ww2.biol.sc.edu/~elygen/biol303/History%20of%20Genetics.ppt
• http://www.cpp.edu/~zywang/genetics1.ppt
• En.wikipedia.org