JBRF Genetic Study

The Goal

The goal of the Genetics Study is to better understand the genetic basis of juvenile bipolar disorder.  Greater comprehension of the biological basis of the disorder will lead to better methods of prevention and treatment.

Genetics 101

The human body is composed of trillions of cells.  Each one of these cells contains chromosomes.  There are 23 pairs of chromosomes in every cell except for ova and sperm, which have only a single copy.  The chromosome pairs are made up of one chromosome inherited from our mother and one inherited from our father, making 46 chromosomes in all.

Diagram of a chromosome in a cell

The chromosomes are made of DNA (deoxyribonucleic acid).  Each chromosome consists of two very long thin strands of DNA chains twisted into the shape of a double helix, resembling a twisted ladder.

The rungs on the DNA ladder are called base pairs. There are only 4 types of DNA bases produced in cells, referred to by their shorthand signatures: A, T, G and C. These 4 bases are strung together, chemically, over and over in a precise manner creating a continuous string of 3-billion bases in every cell in every person. This constitutes the human genome. The base pairs are essentially a set of instructions given to cells.  The order of the base pairs serves the same purpose as the order of letters on a page – only instead of connecting letters to form words, DNA bases connect and communicate biological information to cells. One is the instruction to make a specific protein, which is guided by a 3-base unit called the genetic code. For example, the 3-base unit ATG instructs the protein synthesizing machinery in a cell to place the amino acid methionine into a growing protein (amino acids are the building blocks of proteins).

Diagram of a gene on a chromosome

Each strand of DNA is really a long string of genes.  Each gene contains the code to make one particular protein. Proteins are the building blocks for most of your body. In the same way that a wall is made mostly of bricks, every cell is made mostly of proteins. Even the parts of a cell that are not proteins, such as carbohydrates and fats, are influenced by them; proteins guide their synthesis and destruction.

We inherit one copy of every chromosome from each parent. Consequently, we also inherit, with some exceptions, two copies of every gene, one from each parent. About 99.9% of the genetic code is identical from person to person. The remaining 0.1% is small variations in DNA between people. It is these small variations – having slightly different genes – that make us all different from each other.

Genes are how we inherit features from our ancestors.  For example, children usually resemble their parents because they have inherited their parents’ genes. If someone has blue eyes it is the direct result of that person having genes inherited from one or both parents that code for proteins that make their eyes look blue.  Another person could have genes that code for proteins that make their eyes look brown. The same is true for all physical characteristics. The different versions of a gene that cause these changes are referred to as alleles.

Another type of information that exists in our genome is determining which genes are active in a particular cell. A different set of genes is active in each cell type creating the extraordinary functional diversity of cells and organs; from skin to brain to eye.

The entire package (genes, DNA, alleles) makes up your genome; a unique personal set of hereditary information handed down from parents, and then transmitted to children.

Genomes change.  They can change between generations or over a lifetime.  These changes are called mutations, which essentially can create new alleles – new modified versions of genes.  A mutation in a gene responsible for skin color, for example, created alleles for dark skin and fair skin color.  Mutations happen by chance during the formation of ova and sperm, and most make no difference at all. However, some mutations drive human evolution, like the changes in the genes responsible for brain development that resulted in our capacity for language and abstract thought. Others cause disease, like cystic fibrosis, sickle cell anemia, and bipolar disorder.

Finding the Genes Responsible Bipolar Disorder: GWAS and Sequencing

There are a number of approaches geneticists have developed to identify genes (actually, the mutated versions of normal genes) involved in genetic disorders. The first step, of course, is to find patients and archive their DNA. Over the past few years, the JBRF has been collecting DNA from children with bipolar disorder, and in some cases, their siblings and biological parents.

One approach to finding unknown genes is called GWAS (short for genome-wide association study). In this approach, geneticists analyze the entire genome for a type of variant called a SNP. A million SNPs are analyzed simultaneously using DNA chip technology. This is a collection of microscopic DNA spots attached to a solid surface, a gene chip. Thousands of patients and control subjects are studied with the goal of finding a few SNPs out of the million analyzes that appear more frequently in the patient population compared with controls. These SNPs often (but not always) pinpoint the precise gene involved, but cannot identify the causal mutation. The SNPs themselves do not directly cause the disease; they are simply “tagging along” with the actual causal variants. For this reason, researchers often need to take additional steps, such as sequencing DNA base pairs in that particular region of the genome, to identify the exact genetic change involved in the disease. GWAS has become the method of choice for identifying disease causing genes in complex traits such as bipolar disorder and other neuropsychiatric disorders.

A small part of a DNA microarray – a technique that fluorescently labels and displays DNA – as many as 500,000 SNPs can be compared at the same time.

Research Next Step

Although GWAS is a very powerful tool for identifying genes involved in complex traits, it has serious limitations, the major one of which is that it can only find common alleles that may contribute to disease. Unfortunately, in bipolar disorder and other inherited psychiatric disorders, common variants are only responsible for about 10-20% of the genetic risk. The majority of cases, it is widely believed, are caused by so-called rare variants – mutations that drastically affect gene function that are found in less than ~1% of the population. Hundreds, perhaps thousands of different rare variants are believed to be responsible for bipolar disorder throughout the world. The same principle holds true for schizophrenia and autism. Collectively, these rare variants are responsible for the overwhelming majority cases. One type of rare variant known to be responsible for ~10-20% of schizophrenia and autism is the so-called copy number variant (CNV), which results in a loss or gain of one or several genes. CNVs can cause bipolar disorder as well, but it’s less common than in these other conditions. The only way to identify rare variants responsible for the overwhelming majority of bipolar disorder (and schizophrenia and autism as well) is to sequence the DNA of affected individuals.  There are two fundamental approaches, both of which will be undertaken by JBRF: exome sequencing and whole genome sequencing.

Exome sequencing essentially determines every letter in a DNA sequence for the portion of the genome called exons. Exons are the parts of a gene that provide instructions for protein production.  Despite their key role in cells, exons only represent about 2% of the human genome. Exons are captured by a type of DNA chip, after which they can be isolated and sequenced.  After sequencing, functional variants can be identified and validated through a variety of complex biological and computer-based technologies. This method is generally carried out on several hundred subjects and controls

While exome sequencing is a very powerful tool for identifying rare variants responsible for disease, it cannot be used to find those that reside in the remaining 98%, the part of the human genome – the so-called non-coding regions (but euphemistically referred to as “junk DNA”). In fact, non-coding DNA contains important genetic information needed for normal cell growth and development. It is widely believed that a substantial proportion of rare variants responsible for bipolar disorder will be found within non-coding DNA,” and the only way to identify them is by whole genome sequencing – the complete deciphering of an individual’s entire genetic makeup.

The capacity to sequence an entire genome has been made possible by breath-taking advances in sequencing technology. About 11 years ago the entire sequence of a human’s DNA was published – which was accomplished by an international consortium that spent more than a decade on the project at a cost of $3-billion ($1/base). Recent advances, however, have reduced the time it takes to sequence a genome to a couple of months, and have brought the cost down to ~$5,000, making it economically feasible to use it as a tool to find rare variants throughout the entire human genome; exons and non-coding regions. However, the biological and computational tools needed to sift through the entire genome to find the precise disease-causing mutation responsible for a disorder in a person is much more daunting than exome sequencing.

Whole genome sequencing is ideal for identifying rare disease-causing mutations in families with multiple affected members.  In this scenario, we would expect to find the same rare, disease-causing variant in all affected members, assuming the illness has been transmitted from a single parent, greatly simplifying, but by no means eliminating, the difficult computational aspects of whole genome sequencing.

With our very extensive clinical network, we have already identified several families who appear to qualify for whole genome sequencing.

In Summary

JBRF will continue to collect DNA from individuals with pediatric onset bipolar disorder and their parents for a triad-based GWAS to capture common variants. The affected children will also be analyzed by exome sequencing to capture rare variants occurring in exons. Finally, we are recruiting families loaded with bipolar disorder for whole genome sequencing in order to identify rare variants occurring anywhere in the genome.

Research can change lives.

Your donation today will move us closer to accomplishing these sequencing studies.  JBRF relies upon your support to continue this very important research.