American Journal of Medical Genetics 100:30±36 (2001) Genetically Determined Low Maternal Serum Dopamine b-Hydroxylase Levels and the Etiology of Autism Spectrum Disorders Paula D. Robinson, 1 Chris K. Schutz, 1,2,3 Fabio Macciardi, 4 Bradley N. White, 1,5 and Jeanette J. A. Holden 2,3,6 * 1 Department of Biology, McMaster University, Hamilton, Ontario, Canada 2 Department of Psychiatry, Queen's University, Kingston, Ontario, Canada 3 Cytogenetics and DNA Research Laboratory, Ongwanada Resource Centre, Kingston, Ontario, Canada 4 Unit of Genetic Epidemiology, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Ontario, Canada 5 Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada 6 Department of Physiology, Queen's University, Kingston, Ontario, Canada Autism, a neurodevelopmental disability characterized by repetitive stereopathies and de®cits in reciprocal social interaction and communication, has a strong genetic basis. Since previous ®ndings showed that some families with autistic children have a low level of serum dopamine b-hydroxylase (DbH), which catalyzes the conversion of dopamine to norepinephrine, we examined the DBH gene as a candidate locus in fami- lies with two or more children with autism spectrum disorder using the affected sib- pair method. DBH alleles are de®ned by a polymorphic AC repeat and the presence/ absence (DBH/DBH) of a 19-bp sequence 118 bp downstream in the 5 0 ¯anking region of the gene. There was no increased concor- dance for DBH alleles in affected siblings, but the mothers had a higher frequency of alleles containing the 19-bp deletion (DBH), compared to an ethnically similar Canadian comparison group (w 2  4.20, df  1, P  0.02 for all multiplex mothers; w 2  4.71, df  1, P < 0.02 for mothers with only affected sons). Although the odds ratios suggested only a moderate relevance for the DBH allele as a risk allele, the attributable risk was high (42%), indicating that this allele is an important factor in determining the risk for having a child with autism. DBH geno- types also differed signi®cantly among mothers and controls, with 37% of mothers with two affected sons having two DBH alleles, compared to 19% of controls (w 2  5.81, df  2, P  0.03). DbH enzyme activ- ity was lower in mothers of autistic children than in controls (mean was 23.20  15.35 iU/ liter for mothers vs. 33.14  21.39 iU/liter for controls; t  1.749, df  46, P  0.044). The DBH allele was associated with lower mean serum DbH enzyme activity (nondeletion homozygotes: 41.02  24.34 iU/liter; hetero- zygotes: 32.07  18.10 iU/liter; and deletion homozygotes: 22.31  13.48 iU/liter; F  5.217, df  2, P  0.007) in a pooled sample of mothers and controls. Taken together, these ®ndings suggest that lowered maternal serum DbH activity results in a suboptimal uterine environment (decreased norepi- nephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum dis- order in some families. ß 2001 Wiley-Liss, Inc. INTRODUCTION Autism is the most severe of a group of pervasive developmental disorders (PDDs), which are character- ized by impairments in reciprocal social interaction, dif®culties with both verbal and nonverbal communica- tion, and displays of stereotypic activities [American Psychiatric Association, 1994]. Collectively, they are referred to as autistic spectrum disorders (ASDs) and include autism, atypical autism, Asperger syndrome, childhood disintegrative disorder, and Rett syndromeÐ conditions that share these features, but differ in the Grant sponsor: Scottish Rite Charitable Foundation; Grant sponsor: Ontario Mental Health Foundation; Grant sponsor: National Science and Engineering Research Council (NSERC); Grant sponsor: Medical Research Council of Canada. *Correspondence to: Jeanette J. A. Holden, Ph.D., Cytogenetics and DNA Research Laboratory, Ongwanada, 191 Portsmouth Avenue, Kingston, Ontario K7M 8A6. E-mail: holden@post.queensu.ca Received 7 June 2000; Accepted 5 December 2000 Published online 27 February 2001 ß 2001 Wiley-Liss, Inc.