Acta Medica International

: 2015  |  Volume : 2  |  Issue : 2  |  Page : 130--134

Genetics in psychiatry – diagnostic support or an illness classification!

Hena Jawaid1, Syed Muhammad Ali2,  
1 Instructor, Department of Psychiatry, Aga Khan University Hospital, Karachi, Pakistan
2 Resident Medical Officer, Sind Institute of Urology and Transplantation, Karachi, Pakistan

Correspondence Address:
Hena Jawaid
Instructor, Department of Psychiatry, Aga Khan University Hospital, Karachi


Psychiatric diseases and their diagnosis are basically dependent upon phenomenology, other than a few conditions where the focus is on purely the medical condition. The changing and evolving picture of psychiatric nosology inculcates genetic findings as well. It has helped clinicians in understanding the disease pathology, its course, prognosis and the intervention options. This comprehensive, pedagogically-oriented review is aimed to include different advancements in genetic association studies along with various terms and findings in psychiatry, which have facilitated deeper understanding of illness at the molecular level. Findings on Alzheimer's disease, Autism spectrum disorder, schizophrenia and eating disorders are discussed. Existing interventions can be further modified by addition of modulators, inhibitors of A-beta aggregation, immunotherapy and inhibitors which can be generated on the basis of genetic association studies and its findings.

How to cite this article:
Jawaid H, Ali SM. Genetics in psychiatry – diagnostic support or an illness classification!.Acta Med Int 2015;2:130-134

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Jawaid H, Ali SM. Genetics in psychiatry – diagnostic support or an illness classification!. Acta Med Int [serial online] 2015 [cited 2021 Nov 30 ];2:130-134
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The Brain Architecture

The nervous system is composed of specialized cells called neurons that are capable of generating and transmitting electrical signals via cellular extensions called axons and dendrites. There are two types of neurons. The sensory neurons, which transmit signals from peripheral receptors to the brain and spinal cord and the motor neurons which transmit signals from the brain and spinal cord to muscles and various glands.

Upon excitation an action potential is generated across the cell membrane of a neuron that travels along the length of the axon, at the end of which there are many small swellings which release chemical substances called neurotransmitters. These chemicals transmit signals from one neuron to an adjacent neuron. Neurotransmitters can be excitatory or inhibitory in their effect. Important neurotransmitters include acetylcholine, norepinephrine, gamma aminobutyric acid (GABA), dopamine and serotonin.

The Division

Grossly, the nervous system can be divided into central nervous system consisting of the brain and the spinal cord and the peripheral nervous system. The latter consists of nerves which connect the CNS to different parts of the body. The peripheral nervous system can further be divided into somatic and autonomic nervous system.

The somatic nervous system involves the sensory receptors and the muscles. While the autonomic nervous system controls the function of internal organs and glands. It can further be divided into sympathetic and parasympathetic divisions. The sympathetic nervous system involves the fight or flight mechanism and is more active during excitement while the parasympathetic system dominates during rest.

Because the autonomic nervous system controls the action of smooth muscles and glands like the pituitary and the adrenals, it is very important in emotional reactions of a person.

The Emotional and Rational Landmarks

Functionally, the brain can be divided into the central core, the limbic system and the cerebrum. The central core comprises of medulla which has respiratory center, the thalamus which relays sensory information, the hypothalamus which helps in maintaining homeostasis and is important in emotion and the cerebellum which is involved in maintaining postural balance and coordination of voluntary movements.[1]

The limbic system has an important role in forming memories and controls various instinctive behaviors and emotions like aggression, sexual and feeding behaviors etc.

The cerebrum consists of the cerebral cortex which is the seat for higher intellectual function, complex thought processes and decision making. Certain areas of the cerebral cortex receive sensory information while others control motor functions of various parts of the body. The cerebrum is divided into a right and left hemisphere by the central sulcus. The left hemisphere has areas associated with language and mathematical abilities while the right hemisphere is associated with spatial perception and a sense of patterns and shapes.

 Recent Terminologies and Advancements


Epigenetics is the study of factors that affect gene expression without altering the DNA sequence itself. Such changes may or may not be inherited by the offspring. Examples include DNA methylation, histone modification and interaction of various proteins with certain silencing sequences in the DNA.

It is the interaction of epigenetic factors with the DNA that result in various phenotypes without any changes being made to the phenotype of a cell. Example: the differentiation of embryonic cells into specialized cells to form different tissues in the body.


When the phenotype of one gene locus is altered or modified by another gene locus the phenomenon is called epistasis. It is the non-additive contribution made by two or more genes for the same phenotype.


Endophenotypes are certain hereditary behavioral traits that are considered to have a strong genetic origin and are present in individuals who have, or are at an increased risk of developing a disease. These characteristics manifest themselves irrespective of whether the disease is actively present or not. They are found at a higher rate in affected families compared to the general population. For example, there is a decline in working memory and pre-pulse inhibition in schizophrenia.

Single Nucleotide Polymorphism (SNP)

Most of the diseases are due to alterations in one or few nucleotide bases of DNA sequence.

Copy Number Variations (CNVs)

These are miniature chromosomal abnormalities which include duplication and deletion of DNA stretches.


Courtesy – Department of Psychiatry, Indiana University School of Medicine Neuroscience Research Building (www.

 Genetic Association Studies

Genetic association studies are of two types

  1. Candidate Gene Studies

  2. It measures frequency of genetic polymorphism.

  3. Genome Wide Association Studies (GWAS).

GWAS is a study in which the entire genome of a group of people who have a particular trait or disease, is examined and compared with the DNA of a similar group of people who do not. These studies involve the identification of small genetic variations, called Single Nucleotide Polymorphisms or SNPs that occur more frequently in people with the disease. The SNPs are then considered for having a possible association with that disease.

 Advances in Genetics: It'S Impact on Psychiatry

Psychiatric illnesses come across with major issues in terms of determination regarding genetics.[2] There is no phenomenon in psychiatric disorder as we see in non-psychiatric illnesses; like one –gene-one-disorder process. Due to non-specification in location and pleiotropic effect; it's hard to localize the essence of origin.[2] Other reasons for the difficulty are: epistasis, gene-gene interaction, allelic heterogeneity and genetic heterogeneity.[3]

Alzheimer's diseases and its pathogenic have opened the door for other psychiatric disorders to be understood under light of genetic associations, impact and outcome. The investigations paved its way further to unveil psychopathological aspects of autism spectrum disorder too.

Alzheimer's Disease

The disease pathology includes dystrophic neuritis which surrounds beta amyloid core is called as senile plaques. Brain parenchyma and blood vessels get rich in tauladen neurofibrillary tangles and congophilic angiopathy respectively. The behavioral outcomes initiate from apraxia, cognitive decline, language difficulties and dysphasia.[4]

Vigorous evidence and research findings came to conclude that genetic basis of Alzheimer's disease can be understood by dividing it into following 2 categories.

1- Familial Form

2- Sporadic Form.

Familial form

This form is characterized by i) high penetrance ii) early onset ii) autosomal dominant inheritance.

Sporadic form

Environmental and genetic contributions determine sporadic autosomal dominant form. The complexity of pathogenesis revealed itself further through advancement in investigations regarding Apolipoprotein E and genome wide association studies.

Candidate gene studies and linkage studies have helped a lot in finding out role of chromosome 21 in Alzheimer's disease.

Chromosome 21 carries Amyloid precursor protein gene, linkage studies marked out mutation in it which consequently results in memory impairment and behavioral dysfunction. Different APP mutations cause accumulation of beta amyloid deposits and senile plaques. Findings also pointed out synaptolysis, astrocytosis, microgliosis and extra cellular concentration of beta amyloid. Although, there were no neurofibrillary tangles observed.

The further suspicion to find out a cause for tangles unwraps through genome wide association studies and linkage analysis of early onset Alzheimer's disease. This resulted in an identification of presenilin-1 (PS-1) on chromosome 14q24.3 and presenilin-2(PS-2) on chromosome 1q. These are trans-membrane proteins with seven trans-membrane domains, with a function of protein processing in endoplasmic reticulum. Inactivation of presenilins can cause neuro-degeneration and memory loss.

Alzheimer's disease pathology was not much understood till 1991 when through linkage studies; susceptibility of involvement of chromosome 19 long arm was noted down. Further on, association studies in 1993 pointed out Apolipoprotein E gene involvement in late onset Alzheimer's disease along with previous observed linkage with chromosome 19.

There are three known alleles of this gene. Namely: e2, e3 and e4. e4 has an incidence of 50 percent in late onset Alzheimer's disease. In genome wide association studies conducted in 2007, it was further found out that GAB2 (GRB-associated binding protein-2) is an additional risk allele in apoE-e4 carriers. The risk increased to 25 fold in presence of both.

Autism Spectrum Disorder

It is a neurodevelopmental disease with the impairments of social interaction, language and with repetitive or stereotyped movements. The genetic basis of this disorder is quite complex. It includes interaction of multiple genetic variants, which increase susceptibility of this syndrome. The small effect generated by variants' interaction is also pointing it as a heterogeneous disorder.

Studies which have helped in revealing out the pathological basis include: whole genome screens, candidate gene studies, chromosome rearrangement studies, mutation analysis and segregation analysis.[5] The three prominent domains of pathology which appeared are:

1- Synaptogenesis and maintenance

2- Cell migration

3- Excitatory or inhibitory neurotransmitter networks.

Synaptogenesis and Maintenance

Neuronal formation

Neuroligin (NLGN) 3, 4 and SHANK 3 genes were found to be responsible for cell adhesion, synaptogenesis and maintenance in autism. It is thought to be caused by chromosomal rearrangement. Neuroligin genes are located on X chromosome. It produces adhesion among post-synaptic glutaminergic neurons. Its mutation can lead towards defective trafficking.

SHANK3 is a binding partner of Neuroligins and serves as structural organizer of dendritic spines. Genomic hybridization studies have marked out large deletions in chromosomes 22q13 which contains SHANK3.

Cell Migration

Linkage studies have shown chromosome 7q as most evident marker of defective cell migration in autistic brains. It contains several genes which are strong candidates for autism namely – RELN (chromosome 7q22) it codes for reelin, which is a signaling protein secreted by marginal zones of developing brain, called as Cajal-Retzius cells. It has important role in cellular migration and neuronal connections. Cytoarchitectural deformities arise on spontaneous deletions of RELN.

WNT2 (wingless type MMTV integration site family member 2) is another gene identified as a candidate for autism. It is located on chromosome 7q31 and responsible for severing signaling proteins which assist brain developmental process including cell regulation and embryogenesis.

Excitatory/Inhibitory Neuronal Transmission Network

Role of gamma amino butyric acid is crucial in this regard. It acts as an inhibitory neurotransmitter in a central nervous system. GABA receptors are present in form of clusters in chromosome 15q11-13. The most common cytogenetic abnormality seen here is duplication, which is a frequent finding in autism (6 percent cases). The region known as 15q11-13 is also important for Angel men syndrome and Prader-willi syndrome.

Eating disorder

Further advancement in genetic polymorphism, chances and variability revealed pathological changes in behavior like eating behavior. The propensity of eating disorder was confirmed through a mutation.

According to senior author Michael Lutter, MD, PhD, a neuroscientist at the University of Iowa's Carver College of Medicine, there is about 50% to 70% of the risk of getting an eating disorder was inherited.[6]Although, the identification of a locus point was a difficult part.

They have recruited large families' genomes to calculate precisely the loci of inheritance as well as mutation and found out rare mutations in the estrogen-related receptor alpha (ESRRA) gene affects ESRRA's expression.

This mutation caused to decrease the activity of the protein expressed by ESRRA. This decrement in protein shows obsessive-compulsive behaviors and social difficulties in interpersonal relationship maintenance and interactions as well as a decreased desire for fat rich foods during a state of hunger.

 Psychiatric Genomics Consortium

The project which was started in 2007 is the largest collaboration in the history of psychiatry named Psychiatric Genomics Consortium (PGC). It has recruited 123,000 samples from people with a diagnosis of schizophrenia, bipolar disorder, Attention deficit hyperkinetic disorder, autism and 80,000 controls were collected by over 300 scientists from 80 institutions in 20 countries.[7]

In 2011, the PGC recognized 5 genetic variants associated with schizophrenia. In 2012, 22 significant genetic markers were surfaced out. Today, it is more than 100 genetic variants which are significant. Although the recognized markers cannot serve as a genetic causes for schizophrenia, but can delineate risk which can contribute to the illness. The presence of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1) has opened an avenue for greater understanding of disease and contributory factors associated with it beside existing neurodevelopmental and known psychosocial factors.[8]

Further studies have revealed significance of electrical impulses and conduction. The existence of theta activity arises from hippocampus moves across the whole brain, in order to coordinate and function effectively. The theta activity causes co-ordination of activity in the hippocampus and prefrontal cortex.

The study which is done by researchers in the Oxford Centre for Human Brain Activity (OHBA) suggests that there is a link associated with a gene, known as ZNF804A. It further clarifies the generation of condition called schizophrenia is due to ZNF804A gene variant effects on theta activity in brain.[9] The impact of ZNF804A on rhythmic theta activity causes impaired co-ordination between the hippocampus- prefrontal cortex, which may serve as a main symptom formation in schizophrenic patients.[10]


Rapid advancement in different diseases and illness phases is introducing psychiatry into a changed paradigm. It will help us to understand genetic influence, co-morbidity and its significance, etiological framework, behavioral neurology and psychiatric classification. Research in genetics is an opportunity for geneticists as well as psychiatrist to deal with disease spectrums in earlier phases by running chromosomal analysis and gene testing. Not only early intervention is a possible option for disease control through this, but the approach can also involve development of antibodies, vaccines and small molecules against the target gene which can resolve most of the queries.

In recent years, major projects of genetic analysis and discoveries of SNPs, CNVs and linkage findings have facilitated the comprehension of psychopathological phenomena. The further advancement in this path would also enable us to find remedies of potential irreversible disease processes.


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