GENETICS IN PSYCHOBIOLOGY

Introduction

• Psychiatric genetics, a subfield of behavioral neurogenetics, studies the role of genetics in psychological conditions such as alcoholism, schizophrenia, bipolar disorder, and autism

• Psychiatric genetics is a somewhat new name for an old question, “Are behavioral and psychological conditions and deviations inherited”. The goal of psychiatric genetics is to better understand the etiology of psychiatric disorders, to use that knowledge to improve treatment methods, and possibly also to develop personalized treatments based on genetic profiles.

• In other words, the goal is to transform parts of psychiatry into a neuroscience-based discipline.

History

• Research on psychiatric genetics began in the late nineteenth century with Francis Galton (a founder of psychiatric genetics) who was motivated by the work of Charles Darwin and his concept of desegregation.

• These methods of study later improved due to the development of more advanced clinical, epidemiological, and biometrical research tools.

• Better research tools were the precursor to the ability to perform valid family, twin, and adoption studies. Researchers learned that genes influence how these disorders manifest and that they tend to aggregate in families.

Genome

• The genome is the entirety of an organism’s hereditary information. It is encoded either in DNA or, for many types of viruses, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA

• An analogy to the human genome stored on DNA is that of instructions stored in a book:

• The book (genome) would contain 23 chapters (chromosomes);

• Each chapter contains 48 to 250 million letters (A,C,G,T) without spaces;

• Hence, the book contains over 3.2 billion letters total;

• The book fits into a cell nucleus the size of a pinpoint;

• At least one copy of the book (all 23 chapters) is contained in most cells of our body. The only exception in humans is found in mature red blood cells which become enucleated during development and therefore lack a genome.

DNA

• Deoxyribonucleic acid (DNA) is a molecule that encodes the genetic instructions used in the development and functioning of all known living organisms and many viruses.

• DNA is a nucleic acid; alongside proteins and carbohydrates, nucleic acids compose the three major macromolecules essential for all known forms of life. Most DNA molecules are double-stranded helices, consisting of two long biopolymers made of simpler units called nucleotides—each nucleotide is composed of a nucleobase (guanine, adenine, thymine, and cytosine), recorded using the letters G, A, T, and C, as well as a backbone made of alternating sugars (deoxyribose) and phosphate groups (related to phosphoric acid), with the nucleobases (G, A, T, C) attached to the sugars.

• DNA is well-suited for biological information storage.

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RNA

• Ribonucleic acid (RNA) perform multiple vital roles in the coding, decoding, regulation, and expression of genes.

• Like DNA, RNA is assembled as a chain of nucleotides, but is usually single-stranded. Cellular organisms use messenger RNA (mRNA) to convey genetic information (often notated using the letters G, A, U, and C for the nucleotides guanine, adenine, uracil and cytosine) that directs synthesis of specific proteins, while many viruses encode their genetic information using an RNA genome.

• Some RNA molecules play an active role within cells by catalyzing biological reactions, controlling gene expression, or sensing and communicating responses to cellular signals.

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Gene

• A gene is the molecular unit of heredity of a living organism.

• Living beings depend on genes, as they specify all proteins and functional RNA chains.

• Genes hold the information to build and maintain an organism’s cells and pass genetic traits to offspring.

• All organisms have many genes corresponding to various biological traits, some of which are immediately visible, such as eye color or number of limbs, and some of which are not, such as blood type, increased risk for specific diseases, or the thousands of basic biochemical processes that comprise life.

RNA genes and genomes in the world-

• When proteins are manufactured, the gene is first copied into RNA as an intermediate product. In other cases, the RNA molecules are the actual functional products.

• For example, RNAs known as ribozymes are capable of enzymatic function, and microRNA has a regulatory role. The DNA sequences from which such RNAs are transcribed are known as RNA genes.

• Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription.

• On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized.

• In 2006, French researchers came across a puzzling example of RNA-mediated inheritance in mice. Mice with a loss-of-function mutation in the gene Kit have white tails. Offspring of these mutants can have white tails despite having only normal Kit genes. The research team traced this effect back to mutated Kit RNA.

Chromosomes

• The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes; the region of the chromosome at which a particular gene is located is called its locus.

• A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded.

DNA and Human Genome Project

• The history of biology was altered forever by the launching of the Human Genome Project, a research program that has characterized thecomplete set of genetic instructions of the human. Science is showing that the complexity of human emotions and behaviour is governed by a variety of genes and their interplay with each other, environmental factors, personality and life experiences (Cole et al, 2010).

• Determined of the DNA sequence for the human gene was completed in April 2003, marking the end of the Human Genome Project, 2 years ahead of schedule. One of the most daunting challenges remaining is that of understanding how all the parts of cells- genes, proteins and many other molecules work together to create complex living organisms in heath and illness (NHGRI, 2011)

• Insights gained from the human DNA sequence:

• The human genome contains 3 billion nucleotide bases (A, C, T, G), combinations of which comprise all genetic codes. The average gene has 3000 bases. Humans have about 30,000 genes (one third as many as previously thought), the same number as found in a laboratory mouse.

• The functions of more than 50% of the discovered genes are still unknown,

• The human genome sequence is almost (99%) exactly the same in all people.

• Slight variations in DNA sequence can have a major impact on the manifestation of a disease process and on responses to environmental factors, such as presence of microbes, toxins and drugs.

• Single-nucleotide polymorphisms (SNPs) are sites in the human genome where individuals differ in their DNA sequence, often only by a single base. Sets of SNPs on the same chromosome are inherited in blocks and may help determine the etiology of disease as well as the efficacy of new treatments.

• The genome, an organism’s complete set of DNA instructions, is organized into chromosomes, which contain many genes, the basic physical and functional units of heredity. Genes are specific sequence of bases that encode instructions on how to make proteins, which are large, complex molecules made up of amino acids. It is the proteins that perform most life functions and constitute the majority of cellular structures.

• Genetic mapping, also called linkage mapping. It can offer firmevidence that a disease transmitted from parent to child is linked to one or more genes, and it provides clues as to which chromosomes contain the gene and where the gene is on the chromosome.

• Genetic testing is a commercial medical application of the newgenetic discoveries, used to diagnose disease, confirm a diagnosis, provide prognostic information about the course of a disease, confirm the existence of a disease in symptomatic individuals, and detect predispositions to disease in healthy individuals and their offspring.

Human genetic variation

• Human genetic variation is the genetic differences both within and among populations.

• No two humans are genetically identical. Even monozygotic twins, who develop from one zygote, have infrequent genetic differences due to mutations occurring during development and gene copy number variation.

• Differences between individuals, even closely related individuals, are the key to techniques such as genetic fingerprinting. Alleles occur at different frequencies in different human populations, with populations that are more geographically and ancestrally remote tending to differ more.

• Causes of differences between individuals include the exchange of genes during meiosis and various mutational events.

• There are at least two reasons why genetic variation exists between populations.

• Natural selection may confer an adaptive advantage to individuals in a specific environment if an allele provides a competitive advantage. Alleles under selection are likely to occur only in those geographic regions where they confer an advantage.

• The second main cause of genetic variation is due to the high degree of neutrality of most mutations. Most mutations do not appear to have any selective effect one way or the other on the organism. The main cause is genetic drift, this is the effect of random changes in the gene pool. In humans, founder effect and past small population size (increasing the likelihood of genetic drift) may have had an important influence in neutral differences between populations.

• Measures of variation- Genetic variation among humansoccurs on many scales, from gross alterations in the human karyotype to single nucleotide changes.

• Nucleotide diversity is the average proportion of nucleotides that differ between two individuals. The human nucleotide diversity is estimated to be 0.1% to

0.4% of base pairs. A difference of 1 in 1,000 amounts to approximately 3 million nucleotide differences, because the human genome has about 3 billion nucleotides.

• •      Single nucleotide polymorphisms- A single nucleotidepolymorphism (SNP) is difference in a single nucleotide between members of one species that occurs in at least 1% of the population. It is estimated that there are 10 to 30 million SNPs in humans.

• SNPs are the most common type of sequence variation, estimated to comprise 90% of all sequence variations. Other sequence variations are single base exchanges, deletions and insertions.

• A functional, or non-synonymous, SNP is one that affects some factor such as gene splicing or messenger RNA, and so causes a phenotypic difference between members of the species. About 3% to 5% of human SNPs are functional. Neutral, or synonymous SNPs are still useful as genetic markers in genome-wide association studies, because of their sheer number and the stable inheritance over generations.

• A coding SNP is one that occurs inside a gene. They occur due to segmental duplication in the genome. These SNPs result in loss of protein, yet all these SNP alleles are common and are not purified in negative selection.

Genes, brain, and behaviour:

• Based on family, twin and adoption studies, it is apparent that both genetic and environmental factors play important roles in the normal development of temperament, personality and attitudes as well as in the pathogenesis of major mental disorders.

• Before the advent of molecular genetics, human behavioural genetics, including investigations of mental illness, were limited to quantitative analyses of twin studies, adoption studies and multigenerational family designs that attempted to discriminate genetic from nongenetic influences on behavioural phenotypes and to determine the modes of inheritance.

• The fundamental challenges facing psychiatric genetics are the difficulty of defining phenotypes and the apparently large number of genetic and nongenetic risk factors involved in producing mental illness phenotypes. Gene-environment interaction may play a role not only in the initial expression of mental disorders but also in their course.

Heritability and Genetics

• The term genotype refers to the total set of genes present in an individual at the time of conception, and coded in the DNA. The physical manifestations of a particular genotype are designated by characteristics that specify a specific phenotype.

• Examples of phenotype include eye colour, height, blood type, and language and hair type.

• As evident by the examples presented, phenotypes are not only genetic but may also be acquired i.e. influenced by the environment, or a combination of both. I is likely that many psychiatric disorders are the result of a combination of genetics and environmental influences.

• Investigators who study the etiological implications for psychiatric illness may explore several risk factors. Studies to determine if an illness is familial compare the percentage of family members with the illness to those in the general population or within a control group of unrelated individuals. These studies estimate the prevalence of psychopathology among relatives, and make predictions about the predictions about the predisposition to an illness based on familial risk factors.

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• Schizophrenia, bipolar disorder, major depression, anorexia nervosa, panic disorder, somatisation disorder, antisocial personality disorder and alcoholism are examples of psychiatric illness in which familial tendencies have been indicated.

• Most psychiatric disorders are highly heritable; the estimated heritability for bipolar disorder, schizophrenia, and autism (80% or higher) is much higher than that of diseases like breast cancer and Parkinson disease. Having a close family member affected by a mental illness is the largest known risk factor, to date. However, linkage analysis and genome-wide association studies have found few reproducible risk factors.

• Studies that are purely genetic in nature search for a specific gene that is responsible for an individual having a particular illness. A number of disorders exist in which the mutation of a specific gene or change in the number or structure of a chromosome has been associated with the etiology.

• Examples include Huntington’s disease, cystic fibrosis, phenylketonuria and Down syndrome.

• Heterogeneity is an important factor to consider when dealing with genetics. Two types of heterogeneity have been identified in association with psychiatric genetics: causal and clinical.

Causal heterogeneity refers to a situation in which two or more causes can independently induce the same clinical syndrome. Clinical heterogeneity refers to when a single cause can lead to more than one clinical syndrome.

• In addition to familial and purely genetic investigations, other types of studies have been conducted to estimate the existence and degree of genetic and environmental contributions to the etiology of certain psychiatric disorders. Twin studies and adoption studies have been successfully employed for this purpose.

• Twin studies examine the frequency of a disorder inmonozygotic (genetically identical) and dizygotic (fraternal; not genetically identical) twins. Twins are called concordant when both members suffer from the same disorder in question. Concordance in monozygotic twins is considered stronger evidence of genetic involvement than it is in dizygotic twins. Disorders in which twin studies have suggested a possible genetic link include alcoholism, schizophrenia, major depression, bipolar disorder, anorexia nervosa, panic disorder, and obsessive- compulsive disorder (Baker, 2004; Gill, 2004)

• Adoption studies allow comparisons to be made of theinfluences of genetics versus environment on the development of a psychiatric disorder, Knowles (2003) describes the following four types of adoption studies that have been conducted:

• The study of adopted children whose biological parent(s) had a psychiatric disorder but whose adoptive parent(s) did not.

• The study of adopted children whose adoptive parent(s) had a psychiatric disorder but whose biological parent(s) did not.

• The study of adoptive and biological relatives of adopted children who developed a psychiatric disorder.

• The study of monozygotic twins reared apart by different adoptive parents.

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• Disorders in which adoption studies have been suggested a possible genetic link include alcoholism, schizophrenia, major depression, bipolar disorder, attention-deficit/ hyperactivity disorder and antisocial personality disorder (Knowles, 2003).

• •     The search for the genes that cause mental illness has been challenging and has stimulated scientific, political and clinical debate (Kendler, 2005).

• An example of a genetically heterogeneous (caused by more than one gene) disorder is the rare form of Alzheimer disease that affects people before age 65 years. Early onset AD affects only about 10% of cases and seems to be linked to mutations in any of three specific genes responsible for amyloid-beta, causing excess deposits of this substance in the brains of the persons with AD.

• Current research on the genetics of mental health and illness is confirming the genetic transmission of mental illness but also confronting many challenges. One challenge is the chronic nature of many mental illnesses and the gradual increase of symptoms and behavioural problems over time, also challenging is the length of time required for therapeutic effects of many treatments (T).

• The proteins surrounding DNA affect which portions of the DNA strand are accessible for transcription. This manipulation of DNA can affect gene activity but does not alter the genetic code. Another complication is that psychiatric illnesses are not caused by simple genetic mechanisms but rather by small, cumulative effects from multiple genes )

• The proposed uses of genetics in psychiatry include the following:

• Developing new drugs that will target molecular regulatorsof gene expression that control neuroproteins and neuroenzymes in brain regions shown to be abnormal in a particular psychiatric illness.

• Conducting gene therapy- the introduction of genes intoexisting cells to prevent or cure disease.

• Implementing studies that use ‘candidate genes’ (clonedhuman genes that are functionally related to the disease of interest) in research procedures in the laboratory.

Implications for Nursing

• It is important for nurses to understand the interaction between biological and behavioural factors in the development and management of mental illness.

• The nurse should have clear understanding of the genetic influences i.e. the hereditary factors that predispose individuals to certain psychiatric disorders.

• The nurse should be in the position to answer questions from patients and families about the genetics of mental illness and to educate them about the accuracy and limitations of current testing procedures

• The nurse can objectively share the current evidence while reminding them that this information is often preliminary, yet growing.