Psychiatric Genomics

By George P. Patrinos

Psychiatric Genomics presents and synthesizes available knowledge in the field of psychiatric genomics, offering methodologies to advance new research and aid clinical translation. After providing an introduction to genomics and psychiatry, international experts discuss the genomic basis of schizophrenia, bipolar disorder, depression, personality disorders, anxiety disorders, addictions, eating disorders, and sleep disorders, among other disorders. In addition, recommendations for next steps in clinical implementation and drug discovery are discussed in-depth, with chapters dedicated to pharmacogenomics and antipsychotics, antidepressants and mood stabilizers, adverse drug reactions, implementation of pharmacogenomics in psychiatric clinics, and ethical issues.

Finally, methods sections provide a solid grounding in research approaches and computational analytics, from using animal models in psychiatric genomics and accessing biobanks, to employing computational analysis, genome-wide association studies (GWAS), brain pathophysiology, and endophenotypes in psychiatric research.

• Thoroughly examines the genetic mechanisms underlying a broad range of psychiatric disorders
• Offers genomic methodologies and analytical approaches supporting new research and clinical translation, including personalized diagnosis and treatment models
• Features chapter contributions from international leaders in the field

• Language: English
• Publisher: Academic Press
• Release date: Mar 18, 2022
• ISBN: 9780128214008

Book preview

Preface

Evangelia Eirini Tsermpini, Martin Alda and George P. Patrinos

According to the World Health Organization, 970 million people worldwide suffer from psychiatric disorders. Psychiatry is one of the most challenging specialties of medicines—pathophysiological mechanisms of most disorders are not well understood, and we have no clinically applicable diagnostic tests. As a result, treatment outcomes are often suboptimal and further complicated by side effects of treatments that may often need to be taken for an extended period. Psychiatric genomics is a rapidly evolving field that aims to shed light on the genetic mechanisms associated with the emergence of a psychiatric disorder. Additionally, it holds promise to help identify the right drug and dose of psychiatric medications based on the patient's genetic background.

This textbook provides an in-depth knowledge of this exciting field of psychiatric genomics and aims to supply the reader with the updated available knowledge clearly and comprehensively. Exciting and important topics are discussed in this book, including genetics of schizophrenia, bipolar disorder, depression, personality disorders, anxiety disorders, and addictions, pharmacogenomics of psychiatric drugs, animal models of psychiatric genomics, methodologies and analytic approaches, brain pathophysiology, as well as endophenotypes and ethical issues in applying psychiatric genomics and pharmacogenomics in clinical practice. In addition, the book dedicates a big part to the rapidly increasing field of bioinformatics and big data and shared heritability among psychiatric disorders. In these 17 chapters, written by internationally renowned scientists whose contributions have taken the progress of the field one step forward, readers can explore and be informed about the latest advances in the above areas.

We hope that the book will help the readers better understand the role of genetic factors in the etiology and mechanistic properties of psychiatric disorders and potentially contribute to the promotion of precision psychiatry through new diagnostic and treatment methods.

The book should be relevant to healthcare professionals and physicians who treat patients with psychiatric disorders and also students, academics, and biomedical scientists who have keen research and/or academic interest in psychiatric genomics.

We are thankful to Ms. Kristi Anderson for her constant and remarkable support and to all authors for their outstanding contributions to this book.

Lastly, we would like to thank the patients who inspired us to dedicate our research to psychiatric genomics. We hope that our overall research and intellectual contribution will ultimately contribute to the improvement of their daily lives.

Chapter 1

Genomics and psychiatry: a historical overview

Alessandra G. Ferrera¹ and John I. Nurnberger², ³,    ¹Indiana University School of Medicine, Indianapolis, IN, United States,    ²Department of Psychiatry, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States,    ³Department of Medical and Molecular Genetics, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract

Psychiatric genetics is a relatively new field that has changed rapidly over the past few decades due to technological advancement and scientific breakthrough. This chapter reflects on the origins of psychiatry, its history, and the history of psychiatric genomics.

Keywords

History; eugenics; molecular genetics; psychiatric genetics; family studies; twin studies; genome wide association studies; polygenic risk scores; sequencing; whole genome sequencing

Introduction

In this chapter, consideration is given to the history of psychiatry and how it merges with the history of genetics/genomics to better understand the development of psychiatric genetics.

The history of mental illness likely predates our ability to form written language. However, in some of the earliest forms of written work we find text providing evidence that humans have been afflicted by diseases of the brain and mind since before the common era (BCE). Among those early forms of documentation is the Ebers papyrus, from a collection of documents dating back to 3400 BCE. Within the papyrus there exists a chapter called the Book of Hearts describing mental disorders and how they affect the heart. The description of these disorders appears to be consistent with what would be described as affective disorders today.¹

When his Heart is afflicted and has tasted sadness, behold his Heart is closed in and darkness is in his body because of anger which is eating up his Heart.

—Ebers papyrus (translated)²

Around 400 BCE the Greek physician Hippocrates theorized that physiological abnormalities may be the cause of mental disorders. Hippocrates is known for the development of the idea that the imbalance of bodily fluids or humors would affect the temperaments: In his scheme black bile was associated with melancholic temperament, yellow bile with choleric temperament, phlegm with phlegmatic temperament, and blood with sanguine temperament. Hippocrates believed that an imbalance of these humors would lead to disease and mental illness. An excess of black bile would lead to symptoms of depression in addition to several other diseases and symptoms. Treatment would consist of balancing these four fluids by changing diet, ingesting, or placing medicine on the body, changing lifestyle or occupation, or by bloodletting.³

Hippocrates also used the term hysteria to designate a misplaced uterus. He described hysteria as abnormal movements of the body related to a restless and poorly positioned uterus. He proposed that the uterus can produce toxic fumes and wander around the body causing tremors, anxiety, difficulty breathing, and convulsions. The main treatment for this disorder was marriage; in that, sexual activity would help to reposition the uterus.⁴

Centuries later, the Roman physician Claudius Galen (CE 130–200) also followed the ideas of Hippocrates and thought an imbalance of humors as well as a wandering uterus would lead to disease and hysteria. Galen expanded on the concept of hysteria, which he describes as follows: I have examined many hysterical women, some stuporous, other with anxiety attacks […]: the disease manifests itself with different symptoms.⁴ Galen’s treatment for these symptoms included purging, using herbs and roots as medicine, fragrances, marriage, and intercourse. Galen’s theories were widely supported by the church and prevailed for hundreds of years.⁴ Church and state became heavily intertwined throughout this time until the ideas of Enlightenment took hold and separation of Church and state occurred around the 18th and 19th centuries.

The Middle Ages

Between the 5th and 15th century CE, while the Christian church dominated health belief systems in Europe, sickness and disease were attributed to the work of demons or spirits. Exorcism and rituals became a way to treat mental illness.⁵

During the early Middle Ages, Rabbi Moshe ben Maimon, also known as Maimonides, was born in Spain in 1135. Maimonides placed the importance of mental illness as equal to that of physical illness. It is believed that after the death of his brother, he experienced a major depressive episode that impelled him to practice medicine. He was a pioneer in his time as he understood the importance of assessing fear and anxiety prior to invasive medical procedures. He also recommended therapy to heal the soul and explained that treatments regarding mental health be administered by trained individuals. The type of therapy he recommended was similar to exposure therapy. Maimonides was a religious man and believed that physicians were instruments of God, clearly combining the disciplines of religion and medicine.⁶

During the latter half of the Middle Ages there was an increased focus on grouping the mentally ill to be taken care of together.⁵ Over time, there was a movement toward housing mentally ill patients in public institutions. In 1247 Europe’s first institution specializing in mental treatment was founded near London; this was Bethlehem Royal Hospital, which became known as Bedlam. The hospital was described as barbaric and coercive regarding the treatment of psychiatric patients.⁷ A number of asylums were established in Europe over the next several centuries. However, even in 1700 mental illness was widely considered to be a consequence of spiritual malaise or demonic possession and witchcraft. Thus treatments largely consisted of rituals and exorcism.⁸

Richard Burton wrote a comprehensive text, Anatomy of Melancholy, published in 1621 followed by several revisions between 1624 and 1651. His work reflects the sentiments of his time. He described individuals suffering from melancholia as showing multiple symptoms with the most prominent being fear and sorrow.⁹ He also describes various causes for melancholia including acts of God, witches, devils, poverty, imprisonment, overindulging in revenge, and wine. However, he also describes inherited behavior patterns as a source of melancholy¹⁰:

Their voice, pace, gesture, looks are likewise derived with all the rest of their conditions and infirmities; such a mother, such a daughter; their very affections Lemnius contends to follow their seed, and the malice and bad conditions of children are many times wholly to be imputed to their parents; I need not therefore make any doubt of Melancholy, but that it is an hereditary disease

—Robert Burton¹¹

This is not the first reference to the familial nature of mental disorders, but it is one of the more distinct historical references to the concept of heritability.

The 18th century

In the late 18th century, prominent members of society adopted a physical explanation of mental illness over the supernatural. There was a movement to dispel the notion that mental illness was caused by evil, demonic possession, or witchcraft.

In 1758 English physician William Beattie published Treatise of Madness, calling for specific treatments to be utilized on patients in asylums, helping make the treatment of the mentally ill by physicians a respectable profession. Beattie was one of the founders of St. Luke’s Hospital in 1751, which he hoped to turn into an asylum that would improve the standard of care. Treatment was not only focused on keeping those that were deemed insane within the confines of a space to protect society but also focused on providing treatment to manage the patient’s illness. He used therapy built on the work of physicians Hermann Boerhaave and Albrecht von Haller to accomplish this.⁸ Battie’s ideas were not well received by all and were challenged by other physicians. However, in challenging the ideas, there was increasing attention to the field that drove other physicians to continue to publish psychiatric texts.⁸

Around this time Franz Josef Gall (1758–1828) developed the theory of phrenology. He proposed that brain areas could be localized and separated into faculties that served specific functions while also affecting the shape of the skull. The importance assigned to each faculty in the brain was thought to be represented by its relative size.⁸ Although phrenology was eventually rejected by the medical community due to the growing amount of evidence against it, phrenology popularized the idea that mental disorders stemmed from the brain.⁸

Then in 1793 French physician Philippe Pinel (1745–1826) developed the idea of Moral Treatment for the mentally ill. The Moral Treatment was based on humane care of the afflicted.¹² The mentally ill were no longer shackled or physically abused; instead, they were provided with more appropriate interventions and social interaction. In the Treatise on Insanity (1806), Pinel developed a nosology of what we would now call psychotic disorders.¹² His ideas led to the reform of the asylum system that predominantly existed in Western Europe during that time.¹²,¹³ As a result of his contribution and advocacy for the humane treatment and management of the mentally ill, Pinel became known as the father of Psychiatry.

Era of enlightenment

During the 16th and 17th centuries, a scientific revolution occurred in Europe encompassing various subjects such as astronomy, mathematics, physics, chemistry, and biology. Following the Scientific Revolution, historians describe an Era of Enlightenment. The above-mentioned advances in psychiatry occurring during the 17th and 18th century encompassed the Era of Enlightenment. Over this period, we saw an increase of separation between science and religion.¹⁴

The 19th century

The term psychiatry was introduced at the very beginning of the 19th century (1808) by a German physician, Johann Christian Reil. The word is derived from Ancient Greek, which means medical treatment of the soul.

It was also during this time that psychiatry became formally incorporated as a branch of medicine. The Association of Medical Superintendents of American Institutions for the Insane was founded in 1844 by 13 asylum directors; this was renamed the American Psychiatric Association (APA) in 1921.¹⁵ The American Journal of Psychiatry is the monthly peer-reviewed journal of the APA. Its first volume was published in 1844; at that time, it was known as the American Journal of Insanity.

Emil Kraepelin clinically defined schizophrenia as dementia praecox in 1893.¹⁶,¹⁷ Kraepelin also played a role in psychiatric genetics by describing clusters of psychotic illnesses within families. He also documented cases of Treponema pallidum and noted that it produced the syndrome of general paresis of the insane, which accounted for a remarkable 45% of asylum admissions in urban public hospitals during that time. We now know this as the rare condition of tertiary syphilis and treat it with high-dose antibiotics.¹⁸ It is worth noting that the first effective treatment of general paresis was infection with malaria, which produced a fever that killed the spirochete before the era of antibiotics.¹⁹

Until the mid-19th century anecdotal evidence was used from individual cases to formulate conclusions; in the latter half of the 19th century, there was a shift in a public health model based on infectious disease that led to the redefinition and reclassification of many diseases.⁸ This change stemmed from single cause findings for many infectious diseases. Having one cause of a disease led to more specific testing, methods of prevention, and treatment.⁸ However, this also led to the idea that if a disorder was not amenable to being defined by a single cause it was classified as a syndrome and not considered a true disease.⁸ Even today, identification of a single cause for psychiatric disease is rare, but it has been identified, for example, in copy number variants (CNVs), such as the 22q deletion.²⁰ Eventually, a multifactorial model for most disorders became a major theme in psychiatric genetics.

The late 19th century was also the period that gave rise to the study of genetics as a discipline. Among others, Gregor Mendel, a friar of the Augustinian order, studied the effects of crossbreeding pea plants. Mendel derived the laws of inheritance in 1865²¹ and established the ideas of alleles (genetic variants at a locus), dominance, and recessivity. Mendel’s work and its subsequent re-discovery in the early 20th century by William Bateson and others established the concepts of homozygosity or heterozygosity. These concepts were used by T. H. Morgan in 1915 and Ronald Fisher in 1930 to develop the principles of population genetics that we still use today.

Around this time, the English scientist Francis Galton was working on the studies of human inheritance of intelligence. He published Hereditary Genius in 1869, which was largely based on the premise that men inherit both physical and mental characteristics. In his study he analyzed the pedigrees of about 1000 men who had demonstrated exemplary achievements. He noted that the relatives of these men demonstrated greater than average achievement as well (though decreasing in proportion to the degree of relationship) concluding that talent runs in families for genetic reasons.¹³

Galton also defined the term eugenics in 1883; his definition of this was judicious mating and the goal was improvement of society through the application of principles of inheritance. The field of eugenics was perverted over the subsequent century in ways that we will describe in the following, but even the origin of the field may be considered to harbor the seeds of its own destruction. Galton himself was quoted in this way: "There exists a sentiment, for the most part quite unreasonable, against the gradual extinction of an inferior race.¹³" There are profound ethical issues posed by the concept and the historical development of eugenics (not least of which is the conflict between individual autonomy and societal good) and we will elaborate on the distinctions between the discipline of psychiatric genetics and the theories of eugenics in the following.

Galton’s ideas captivated the scientific community including his cousin, Charles Darwin. Darwin cited Galton as the man who discovered that genius is inherited.²² Darwinists at the time postulated that social characteristics that were undesirable, such as poverty, were assignable to problems in individual human behavior and were substantially hereditary; this idea is also known as Social Darwinism.²² This in turn led to the belief that reproduction should be encouraged in persons with desirable traits and that those who possessed harmful traits should be limited in their capacity to reproduce. However, at that time, selective reproduction measures were thought of as infeasible.²²,²³

The 20th century

At the turn of the 20th century, Karl Pearson, well known for his development of biostatistical methods, published over 300 works on eugenics.²⁴ These works became the source of eugenic science, which was eventually accepted throughout England first, and then around the world. Eugenics helped advance the idea that there exists a genetic aspect to psychiatric disorders. Unfortunately, over time, the theories of eugenics were appropriated in the service of antidemocratic, racist, and scientifically misguided movements, and the notion of selectively breeding (or sterilizing) humans to improve the genetic composition of populations led to abuses that still reverberate today.

Psychiatrists played a major role in the implementation of eugenic concepts, most notably in Germany. Hitler’s document The Law for the Prevention of Offspring with Hereditary Diseases was created in 1933 to specifically prevent the propagation of persons in the German population who suffered from intellectual disability, schizophrenia, and alcoholism.²⁵ This law called for mass formal registration of those afflicted with the aforementioned diseases and forced sterilization of those deemed to be unfit. The court would find an individual unfit if they suffered from a variety of conditions (many of which we know today to not be highly heritable).

The Nazi euthanasia program called for the killing of patients in psychiatric hospitals by gas, lethal injection, and starvation.²⁶ German leaders in the field of psychiatry decided which patients would meet criteria for euthanasia, and German psychiatrists and nursing personnel unfortunately carried out the murder of patients in institutions from the 1930s until the end of the Second World War with a pause in the late 1930s attributable to courageous objections by the German Catholic Church.²⁶ During this time there was a strong focus on euthanizing the mentally ill or handicapped.²³ The Genetic Health Courts would decide which citizens would be sterilized.²⁵

Eventually this program expanded into a movement based on the concepts of racial and religious inferiority.²⁵ When the Nazi regime began implementing the Final Solution for Jews, Gypsies, and other undesirable members of society (such as homosexuals), psychiatrists were often chosen to serve the State by performing triage of individuals entering concentration camps, since the psychiatrists were experienced in such functions based on their work in State Hospitals. Several Nazi physicians were psychiatrists, and this history is unfortunately intertwined with the history of psychiatric genetics.²⁵

Popular belief in eugenics reached the United States early in the 20th century. Many of these concepts were promoted as health initiatives²³ and they were initially widely accepted. In 1927 the U.S. Supreme Court gave the states power, through the decision in Buck v. Bell, to enforce laws that were created to inhibit propagation of those who were mentally ill. The law itself prohibited the marriage of lunatics, imbeciles, epileptics, the insane, and the weak minded.²⁵ These laws remained present for decades, some until the 1980s.²⁵ As a result, thousands of individuals deemed insane were sterilized (generally without informed consent) in the United States between 1907 and 1940.²⁵ The authors’ State of Indiana had one of the earliest sterilization laws and notably an active law that was not repealed until the 1970s. The reputation of eugenics was corrupted during and after the Second World War as it became associated with racism and with the murderous policies of the Nazi era.

During the early to mid-20th century, other trends in psychiatric genetics were simultaneously underway. Family studies were conducted during the early 20th century, first in Europe and then in the United States²⁷ These types of studies allowed investigators to view inheritance patterns of related individuals that extended beyond the parent–child relationship.

In 1916 Ernst Rudin, a prominent figure and eugenics advocate, published a large-scale family study of dementia praecox (schizophrenia) that involved 755 pts with schizophrenia and their 2732 siblings. Rudin continued to expand his studies to include a wide range of more distant relatives such as grandchildren, nieces, nephews, and additional disorders such as personality disorders, affective illness, and obsessive-compulsive disorder.²⁸ Rudin assumed that heredity was the principal cause of mental illness. He wanted to prove that a Mendelian form of inheritance existed for mental illness and to generate the estimates of genetic risk. Unfortunately, he used his results to push for regulation of marriage and sterilization of those he deemed unfit, leading to the Law for the Prevention of Hereditarily Diseased Offspring in Germany.

Family studies demonstrated that the rate of schizophrenia was higher in the relatives of patients with schizophrenia than in the general population in 1933.²⁷,²⁹ However, such studies were unable to separate genetic from environmental influences within the family.³⁰

Twin studies

But twins have a special claim upon our attention; it is, that their history affords means of distinguishing between the effects of tendencies received at birth, and of those that were imposed by the special circumstances of their after lives.

—Francis Galton (1875)³¹

Twin studies can help us understand how genetics and environment contribute to disease. In 1928 Hans Luxenburger performed one of the first twin studies reviewing over 16,000 medical records and identifying same sex twin pairs (10 monozygotic and 13 dizygotic). He noted a higher concordance (both twins suffer from schizophrenia) rate in monozygotic twins as compared to dizygotic. However, the concordance of monozygotic twins was only about 58% suggesting a prominent environmental component.³¹

A significant genetic contribution to schizophrenia was also demonstrated by other twin studies at the time from Franz Josef Kallmann and Eliot Slater.²⁹,³²,³³ In 1946 Kallmann published, The Genetic Theory of Schizophrenia. He used extensions of twin studies to determine the likelihood that a family member will develop schizophrenia. He studied monozygotic twins, dizygotic twins of the same sex, dizygotic twins of opposite sexes, full siblings, half-siblings, and stepsiblings.³² He concluded that the closer the genetic relationship the higher the chance of developing schizophrenia.²⁹,³²

Eliot Slater studied schizophrenia and also investigated the inheritance of bipolar affective disorder. He published a book titled, Psychotic and Neurotic Illness in Twins in 1952. He is also known for advocating a monogenic view of schizophrenia in which the disease was caused by a single (likely) dominant gene. He published his work detailing his monogenic theory in 1958.³³

The twin studies by Kallmann, Luxenburger, and Slater in the early to mid-20th century set the stage for contemporary genetic research in psychiatry. These studies still were unable to definitively separate familial environmental influences (which arguably are more similar in identical twins than fraternal twins) from genetic factors. It remained for adoption studies to provide a strongly convincing case to the scientific and medical communities.³³

Adoption studies

One of the first studies of adopted offspring of mothers with a diagnosis of schizophrenia was conducted in Oregon (the United States) in 1966. The study included 47 individuals adopted shortly after birth and then traced to adulthood. Rates of illness were then compared to illness in 50 adopted offspring of mothers without psychiatric illness. There was a significant increase in the diagnosis of schizophrenia in those adoptees whose mothers were also schizophrenic as compared to the control group.³⁴,³⁵

Seymore Kety’s work beginning in the 1960s (together with collaborators in Denmark and the United States) on genetics of schizophrenia was most influential. During this time, it was known that schizophrenia ran in families, but there was also a widely held belief that schizophrenia was something one could acquire from one’s parents as if it was contagious, like measles, or that it could be imposed on a person by ineffective or malicious parenting.³⁶,³⁷ There was resistance by researchers to the idea that genetics was highly influential in the development of this disease.

Kety noted the higher concordance between monozygotic twins and dizygotic, which argued for a probable influence of genetics in its development.³⁵,³⁸ However, his true contribution was the adoption studies focused on gathering a national sample of all adopted individuals and identifying those that had schizophrenia. This work was aided by the existence of national registers of adoption and separate registers for psychiatric hospitalization in Scandinavian countries. He collaborated with psychiatrist Paul Wender, psychologist David Rosenthal, and the Danish scientist Fini Schulzinger. Together they conducted studies for over 30 years.³⁶ Their studies used multiple models, including the observation that individuals born to schizophrenic mothers and raised in adoptive households developed schizophrenia at the same rate as those raised by their biological mother (with schizophrenia).³⁸

Other strategies included crossfostering, which included adopted offspring of normal biological parents that are raised by parents with schizophrenia. The group is then compared with the adopted offspring of normal biological parents raised by normal (nonschizophrenic) parents and the adopted offspring of schizophrenic biological parents raised by normal adoptive parents.³⁸ Overall, this type of study showed that there is a greater prevalence of mental illness in the adopted-away offspring of biological parents with schizophrenia versus those who were in the crossfostered group.³⁸ In other words, the strongest sources of variance in outcome were genetic rather than environmental.

Modern family studies

Family studies in the early 20th century were found to be useful in adding to our understanding of psychiatric disorders. These studies then prompted twin studies and then adoption studies that ultimately brought about the idea that an individual’s genetic profile can lead to psychiatric illness. As these ideas were developing, Watson and Crick published the double helical model of DNA structure (1953), giving rise to the decoding of protein formation as elaborated by Kornberg and Ochoa, and then Khorana, Holley, and Nirenberg (resulting in Nobel Prizes in 1959 and 1968, respectively, along with the 1962 prize to Watson, Crick, and Wilkins). With this body of work, human genetic influences became tied to specific molecules and mechanisms, and identification of specific genetic factors became a compelling scientific goal.³⁹

In the 1960s, there were also independent advances in the study of the neurobiology and neurochemistry of disease. Psychiatric biological research during this time focused on the understanding of neurotransmitters.³⁸ Later understanding of pathways for neurotransmitter metabolism, transmitter action at specific receptors, and mechanisms of synaptic transmission and intracellular signaling gave rise to a set of natural hypotheses of psychiatric illness that were productive in terms of psychopharmacologic treatments but largely misleading in stimulating candidate gene studies in psychiatric genetics.⁴⁰,⁴¹

DNA sequencing

Nucleotide sequencing provides information about an individual’s genetic makeup. In 1971 the first nucleotide sequence was obtained from bacteriophage DNA—this was 12 nucleotides in length. Over time entire genomes including millions to billions of nucleotides have been deciphered. Sequencing the human genome created a physical genetic map,³³ and this map has been updated periodically as our understanding of the structure and variation in the human genome has become more precise.

In 1982 the identification of the gene responsible for Huntington’s Disease using genetic linkage techniques followed by fine mapping using molecular genetic methods was a watershed discovery that showed the potential of genetic methods to identify the molecular basis of human diseases. This work led to extensive attempts at locating genes that confer risk for psychiatric disorders in a similar way to the Huntington’s gene over the subsequent two decades.⁴²

Linkage studies identify DNA sequences located closely on a chromosome that tend to be inherited together. Linkage studies were conducted to find a single gene that would cause psychiatric illness. However, with time it became evident that the genetic basis of psychiatric illness does not follow the same pattern that is seen with Mendelian disorders like Huntington’s and cystic fibrosis.³⁸ It is now clear that psychiatric disorders are much more complex in their genetic makeup and that environmental influences²⁹ are often important.

In 1988 the National Institute of Mental Health (NIMH) established the NIMH Center for Collaborative Genomic Studies on Mental Disorders. The main purpose of this entity was to increase the amount of human genetic samples and data produced for research. The NIMH Repository and Genomics Resource (now maintained at Rutgers University) has played a major role in psychiatric genetic research by processing and storing a large number of patient and control tissue samples (about 200,000) to provide a source of DNA for multiple psychiatric illnesses.⁴³,⁴⁴

21st century

By the 21st century it was established that psychiatric illness had a genetic component. A large body of work pursuing simple genetic hypotheses, however, had not been successful in identifying specific genetic factors and mechanisms.

The International HapMap project, launched in 2002, was a collaboration between scientists from various countries with the intention of identifying genetic variations between people. The project investigated single nucleotide polymorphisms (SNPs, representing variations in the DNA sequence at a single nucleotide position). The human genome carries 4–5 million SNPs.⁴⁴

Blocks of SNPs that can be inherited together are called haplotypes. The project generated a list of haplotypes, their location on the genome, and their frequency in populations from various countries.

Companies started to produce SNP arrays that could genotype multiple markers in one assay.⁴³ These technological advances led to improvement in the efficacy and cost of data collection. They also provided the impetus and the resources that have allowed genome-wide association studies (GWAS) to be performed (see the following).

Human genome project

Complete human genome sequencing became feasible in 2003, with the completion of the Human Genome Project. Founded by the US Department of Energy and the National Institutes of Health (NIH), this was a 13-year-long project (1990–2003). This project was necessary to continue to discover the complex genetics of human disease, but it also drove progress in the technology used to genotype and sequence genetic information. This increased efficiency lowered cost, allowed for larger studies, and enabled a more complete assessment of genetic variation in man.⁴³–⁴⁵

Genome-wide association studies

GWAS allowed researchers to identify loci that were associated with risk across the entire genome instead of just within one gene of interest.⁴⁴ This method has led to the detection of genomic variants associated with complex traits in a population.⁴³ GWAS has led to the identification of hundreds of common variants that correlate with illness/traits. The first results from GWAS were reported in 2005.⁴⁴ Currently there are over 2000 loci that are associated with a complex trait.⁴⁶–⁴⁸ Using GWAS to establish association between an SNP and a disease requires a very substantial sample size⁴⁶,⁴⁷ to account for the large number of statistical tests that are performed. Typical GWAS studies now include tens of thousands of subjects or more.

These studies have identified thousands of SNPs and other variants related to disease. However, when used to predict risk, individual SNPs have poor predictive value. Using hundreds of variants to generate a Polygenic Risk Score (PRS) makes it somewhat more predictive.

PRS are calculations that can assess an individual’s genetic risk for developing a disease that is complex. PRS does this by summing up the effects of individual SNPs.⁴⁹

Consortia

Consortia for psychiatric genetics led to the formation of large international groups of scientists and researchers who agreed to share data in order to make discoveries. Consortia have been useful in achieving large sample sizes for GWAS studies to provide adequate statistical power for genome-wide studies.³⁵,³⁸ As a result of these large GWAS studies, hundreds of common SNPs associated with psychiatric disorders using strict statistical criteria have been confirmed.⁴⁴

During the years 1970–2000 molecular genetic research in schizophrenia (and other psychiatric disorders) was extensive but not highly productive because of technical limitations and oversimplified hypotheses. Over the past several decades, genetic research in schizophrenia has developed robustly and rapidly, yielding results that may have predictive value. It is evident that schizophrenia is best accounted for by a polygenic model.⁵⁰ Experts agree that for those disorders studied in genome-wide linkage scans of reasonable size and quality—especially schizophrenia, bipolar illness, panic disorder, and eating disorders—conclusive evidence has accumulated that even moderately rare genes of Mendelian-like effect do not exist—Kendler,