Molecular Genetic Studies of Childhood Onset Neuropsychiatric Disorders

Edwin H. Cook, Jr., M.D.
Professor of Psychiatry, Pediatrics and Clinical Pharmacology
Director, Laboratory of Developmental Neuroscience
University of Chicago

Sometimes being a molecular geneticist studying childhood onset neuropsychiatric disorders seems like being the proverbial stranger in a strange land. It was either be a child psychoanalyst or a molecular geneticist and the training for the latter was shorter. Seriously, child and adolescent psychiatry is an interesting field where the level of family and community cannot be ignored while studying molecular genetic contributions to childhood psychopathology.

The laboratory I direct goes back to the interest of Daniel X. Freedman in neurochemistry in autism and other psychiatric disorders in the late 1950s. The laboratory continues to perform, with some updating, the same assay of whole blood serotonin. Since the mechanism of this finding has remained elusive, the movement to molecular genetics to explain this and other neurochemical findings in child and adolescent psychiatric disorders recently moved to the next level when a colleague shared her time and her families to perform a genome-wide screen for whole blood serotonin.

The Laboratory of Developmental Neuroscience is currently involved in the study of genetics as a tool to determine etiology in disorders with the purpose of more rational psychopharmacology. Disorders as complex as autism are ideal for molecular genetic study. In fact, molecular genetics is one of the rare occasions when there is an advantage to studying children. Colleagues such as Judy Cho (inflammatory bowel disease) and Nancy Cox (diabetes) studying complex disorders at the University of Chicago usually have to work around the absence of parents available for the research. In child and adolescent psychiatry, parents are usually more available. In work with Greg Hanna (University of Michigan) in early onset obsessive-compulsive disorder, very large families haye been ascertained from studying younger probands.

Because of outstanding collaborators, the laboratory is able to study many of the child and adolescent psychiatric disorders with highest evidence of heritability. With psychologist Mark Stein, the laboratory was the first to find evidence of linkage between the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD). Since his move to Children's National in Washington, D.C., our team continues to collaborate with Mark with Keith McBurnett taking over the clinical work with ADHD at the University of Chicago. We are continuing to work on confirming susceptibility loci identified by others and in mapping to find the specific susceptibility variant pointed to by the original linkage disequilibrium finding between the dopamine transporter and ADHD.

The toughest part of molecular genetics is finding well-characterized families. Therefore, it has been a pleasure to work with Barbara Geller on early onset bipolar mood disorder, who has diligently collected such families over many years. She is combining prospective longitudinal phenomenology with molecular genetics to understand this frequently severe disorder.

It's a pleasure to work on autism at the University of Chicago with my mentor Bennett Leventhal and colleague Catherine Lord, as well as many junior colleagues including Catherine Jaselskis, Thomas Owley, and Soo-Jeong Kim, as well as numerous colleagues at other universities here and overseas. Autism research takes up a considerable amount of our time. It has also provided some interesting surprises. Not too long ago, it seemed strange to have to write on a consent form that we would tell parents if we found something of clinical significance in the research studies. However, attempts to segregate research and clinical work proved futile when a patient was identified with a maternally derived interstitial duplication of 15qll-ql3. This led to an understanding that paternal duplications of this region were relatively unaffected, while 15qll-ql3 duplications were associated with autism spectrum disorders. The next step will be to understand if there is a different clinical course with 15q11-q13 duplications, as there appears to be, and to determine whether different medications may be helpful for treating the frequently associated anxiety with preoccupations and routines that occurs in these duplication cases.

Another example of clinical relevance was the identification of the most severely truncated MeCP2 protein in a patient in our autism clinic less than a month after publication of the Rett syndrome gene. Although this hasn't changed treatment for this child, the parents are relieved to know the cause of their child's problems and to know that several sisters are at negligible risk of having a child with a related problem.

A marker at the GABA(A) beta 3 subunit gene on l5qlI-q13 was found to be in linkage disequilibrium with autism. Although some studies have been equivocal, the overall evidence at this locus is strong, particularly based on a replication by Joseph Buxbaum at Mt. Sinai. The laboratory is involved in sequencing the third intron and promoter of this gene, screening for mutations, and fine mapping along 15q11-q13. Other findings in autism genetics have included linkage to chromosome 7 working in the International Molecular Genetic Study of Autism Consortium and contributing to fine mapping necessary to move from linkage to susceptibility variant.

There are many misconceptions about genetics. Genetics is not deterministic, as PKU reminds us. More importantly, hanging out with population geneticists has helped lead to an understanding that genetics says much more about inclusiveness than its usual portrayal as a discriminatory tool. First of all, children with autism and related disorders are already among the most discriminated against in society. More importantly, complex genetics shows that most people are likely to have "autism" genes, but only some have sufficient dosage or combination of risks without protection to lead to the disorder. It is likely that most of the variants have an adaptive value, at least in some contexts. It isn't hard to see that the gene that may contribute one more risk for autism may in another context provide the focused attention to pursue research questions in spite of many distractions and occasional disappointment.

The future for molecular genetic research is very exciting in child and adolescent psychiatry The imminent completion of human genome sequencing and developments in understanding of epigenetic regulation (see May 25, 2000 Nature papers by Bell and colleague and Hark and colleagues for the latest twist in imprinting regulation - there is an analogy between the reversals of psychodynamic understanding and the repression of maternal expression of the Igf2 by the enhancer-blocking effects of an insulator) are only two examples of the rapidly evolving tools of molecular genetics available to be applied in finding some of the specific causes of severe mental disorders of childhood onset.