Bipolar Disorder. Bipolar disorder (BD) is a common and disabling disorder characterized by extreme mood swings from mania to depression. Manic symptoms include irritability, inflated self-esteem, euphoria, grandiosity, little need for sleep, talkativeness, distractibility, overly-focused goal-directed activities, and excessive involvement in activities of extreme pleasure regardless of consequence. The depressive symptoms include depressed mood, no enjoyment of activities, reduced sleeping patterns, irritability, fatigue, feelings of worthlessness or excessive guilt, inability to concentrate, indecisiveness, and recurrent thoughts of death or suicide. Tragically, suicide occurs in 10%-15% of individuals who receive a BD diagnosis. BD places a massive burden both on the individual and their family. Unfortunately little is understood about the pathophysiology of BD. This has made the development of new medications a trial and error process, as is, the treatment of individual patients.

While the cause of BD is largely unknown, multiple twin and family studies find that BD has a clear and recognized genetic component. This is evidenced by a 61-75% concordance rate for identical twins. Adding further support, the risk to first-degree relatives is estimated to be 7 to 15%, whereas the lifetime prevalence is estimated at approximately 1-2% in the overall population. Importantly, the mode of inheritance of BD is complex and likely to involve multiple genes. The specific number of susceptibility loci, the recurrence risk ratio attributable to each locus, and the degree of interaction between loci are unknown. The strong heritability of BD suggests a strong role of genes and that knowledge of the genes involved in BD may elucidate its pathophysiology.

Autism. Autism is the leading childhood developmental disorder in the United States with an estimated prevalence between 1 in 166 to 1 in 1000 births. The clinical diagnosis is characterized by findings of a lack of social interaction, stereotypical and/or ritualized patterns of behavior, and the presence of a verbal communication deficit. The presence of autism is typically ascertained between two to three years of age and requires a series of observational and interview-based exams that severely limit the ability to diagnose this disorder early in life. Autism is a complex disease with a clear genetic component and a likely environmental trigger or co-factor. This is indicated by the demonstrated >70% concordance risk in monozygotic twins and a >75-fold increased risk in non-twin siblings.

The diagnosis of autism relies solely on clinical presentation of symptoms as there are no accepted diagnostic biological markers. This diagnosis is typically achieved through the combined scoring of the interview-based, Autism Diagnostic Interview-Revised (ADI-R), and the observation-based, Autism Diagnostic Observation Schedule (ADOS). Autism typically entails (i) qualitative impairment in social interaction; including deficiencies in the use of nonverbal behavior, a failure to develop proper peer relationships, a lack of spontaneous enjoyment or interests with others, and a lack of emotional reciprocity, (ii) qualitative impairment in communication; including a delay in spoken language development, an inability to initiate or sustain a conversation with others, a repetitive use of words or phrases, and a lack of “make believe” play, and (iii) repetitive or stereotyped patterns of behavior; including abnormal preoccupation, adherence to routines, and repetitive motor mannerisms.

Strong evidence supports a heritable component to autism etiology. Family studies support the recurrence risk to siblings to be 1-3%, significantly higher than the risk to the general population, ~0.5-2/1,000. Twin studies have further supported the importance of genetic factors in the etiology of autism. Depending on either narrow or broad phenotype, the concordance rate when one monozygotic twin is diagnosed with autism is 70-90%. In contrast, a 0-25% concordance rate is observed among same-sex fraternal twins. Lastly, the overlap of autism with known genetic disorders further supports a genetic predisposition to autism.

Tools and technology. The high heritability of autism, bipolar and many other neurological diseases combined with emergence of revolutionary genomic technologies provides a unique opportunity to improve our understanding of the pathophysiology for these devastating disorders. Moreover, identifying inherited mutations for a disorder will provide new biologically based diagnostic tools for physicians as well as novel mecular targets for development of treatments. Two competing models exist to explain the genetic basis of complex disease; the common variant and the rare variant hypotheses.

Under the common variant hypothesis, genetic predisposition to a disorder is due to a genetic variant frequently found in the population. For example, the Apoe-4 variant is found in 20-25% of Caucasians and increases one’s relative risk for Alzheimer’s disease by a factor of 3 to 30. Other disorders with identified common genetic variants include Schizophrenia (DRD3), Multiple Sclerosis (HLA-DR), and Diabetes (HLA). The ability to screen the majority of the genome for common variants predisposing to a disease is now possible through high-throughput high-density genotyping technologies of single nucleotide polymorphisms (SNPs). These SNP arrays allow for sequencing (or genotyping) for thousands to millions of positions in the human genome known to commonly differ between individuals. Moreover, genotyping these SNP indirectly provides information about neighboring markers since neighboring markers frequently co-segregate together throughout evolutionary history.

Under the rare variant hypothesis complex diseases arise from a large number of rare genetic variants at many loci. Examples of these types of disorders may include mutations within BRCA1 and BRCA2 for breast cancer where several hundred suspected risk variants are known to occur – recognizing, however, that some mutations in these mutations are common (such as occurs also in BRCA1), particularly in sub-phenotypes or population isolates. Next-generation sequencing technologies are emerging to allow for massively parallel interrogation of large regions of the genome across large numbers of individuals. These advances in sequencing technology will be critical as we search for unexpected changes in any individual’s genome leading to the development of neurological disease.

While providing immense power, these experimental tools for scanning a person’s genome generate massive amounts of data that require development of novel analysis software. As such, a major portion of our research is focused on developing not simply experimental tools, but also computational tools for processing through the large amount of genetics data obtained in the course of sequencing human genomes. As part of developing software for studying neurological disease, we are also involved in several large-scale efforts to study human genetic variation among normal individuals, such as the 1000 Genomes Project.

Together, we believe that the combination of computational and experimental genomic tools for studying the genetic basis of disease will lead to improved diagnosis and better treatment for individuals and family members suffering with neurological diseases.