SEMINAKS I N NEUKOLOUMF.
11, NO. 1
M A R C 1991
Genetics of Learning Disabilities
Our understanding of the genetics of learning disabilities (LDs) has increased dramatically in the last 10 years. This increase in genetic understanding has helped place these previously ill-defined entities, whose very existence had been disputed, squarely on the research agenda for developmental neuroscientists. It is now commonly accepted that LDs (like dyslexia) and other developmental disabilities (like autism and mental retardation) are all neurodevelopmental disorders or, more metaphorically, birth defects of the mind, in which the main impact is on the development of cognition and behavior. Moreover, a genetic change that leads to a specific learning disorder holds the promise of being a special kind of experiment of nature, an exquisitely precise one, in which a single causal pathway that runs from gene to brain to behavior may be perturbed. Unlike the much cruder natural experiments usually provided by acquired lesions, genetic lesions may not "cut across the grain" of development. Besides its clinical interest, therefore, the study of genetic influences on LDs holds considerable promise for addressing basic questions about the mechanisms of brain and behavioral development. On general principles, it should not be too surprising that there are genetic influences on LDs. Of the roughly lo5 structural genes in the human genome, approximately 40% are uniquely expressed in the central nervous system (CNS), whereas many of the remaining 60% are expressed in the CNS as well as elsewhere in the body. We have no reason to suppose that the genes expressed uniquely in the CNS are less polymorphic than other genes; in fact, there are good reasons for supposing they are more polymorphic. Population geneticists have learned that, contrary to earlier beliefs, there is considerable genetic variation both within and across human populations;
behavioral geneticists have documented moderate heritability (about 0.50) for most human cognitive and personality traits.'.' One can almost deduce genetic influences on LDs from these facts. Specifically, if the following three premises are true, it follows logically that there are genetic influences on LDs: (1) There is normal variation in a skill necessary for learning (reading, for example); (2) there is a culturally defined threshold on the normal curve for that skill, so that individuals falling below that threshold will have clinically significant learning problems; (3) across the range of variation, part of the variation is due to heritable influences. T h e first two preniises have solid empirical support; it is well-documented both that there is normal variation in reading, mathematics, and other academic skills and that there are genetic influences on this normal variation, even independent of genetic influences on IQ.3 T h e third premise, although likely, is a separate question. Conceivably, only subclinical (suprathreshold) variation could be genetically influenced, with all subthreshold cases due to environmental causes, both biologic and social. Thus, although we can almost derive logically the fact of genetic influences on LDs from what we already know about the behavior genetics of normal variation in academic skills, we still need direct evidence. i h e r e are two main strategies for obtaining this direct evidence. One is to begin with the phenotype and work backward to the genotype; the other is to begin with a known genotype and examine whether its phenotype includes a specific LD."5 Both strategies have been fruitful and have yielded direct evidence of genetic influences on LDs. In what follows, we will review results coming from each strategy and then conclude with a section on clinical implications.
Professor of Psychology, Psychology Department, University o f Denver, Denver, Colorado Reprint requests: Dr. Pennington, Psychology Department, University of Denver, Denver,
11, NO. 1
M A R C 1991
Genetics of Learning Disabilities
Our understanding of the genetics of learning disabilities (LDs) has increased dramatically in the last 10 years. This increase in genetic understanding has helped place these previously ill-defined entities, whose very existence had been disputed, squarely on the research agenda for developmental neuroscientists. It is now commonly accepted that LDs (like dyslexia) and other developmental disabilities (like autism and mental retardation) are all neurodevelopmental disorders or, more metaphorically, birth defects of the mind, in which the main impact is on the development of cognition and behavior. Moreover, a genetic change that leads to a specific learning disorder holds the promise of being a special kind of experiment of nature, an exquisitely precise one, in which a single causal pathway that runs from gene to brain to behavior may be perturbed. Unlike the much cruder natural experiments usually provided by acquired lesions, genetic lesions may not "cut across the grain" of development. Besides its clinical interest, therefore, the study of genetic influences on LDs holds considerable promise for addressing basic questions about the mechanisms of brain and behavioral development. On general principles, it should not be too surprising that there are genetic influences on LDs. Of the roughly lo5 structural genes in the human genome, approximately 40% are uniquely expressed in the central nervous system (CNS), whereas many of the remaining 60% are expressed in the CNS as well as elsewhere in the body. We have no reason to suppose that the genes expressed uniquely in the CNS are less polymorphic than other genes; in fact, there are good reasons for supposing they are more polymorphic. Population geneticists have learned that, contrary to earlier beliefs, there is considerable genetic variation both within and across human populations;
behavioral geneticists have documented moderate heritability (about 0.50) for most human cognitive and personality traits.'.' One can almost deduce genetic influences on LDs from these facts. Specifically, if the following three premises are true, it follows logically that there are genetic influences on LDs: (1) There is normal variation in a skill necessary for learning (reading, for example); (2) there is a culturally defined threshold on the normal curve for that skill, so that individuals falling below that threshold will have clinically significant learning problems; (3) across the range of variation, part of the variation is due to heritable influences. T h e first two preniises have solid empirical support; it is well-documented both that there is normal variation in reading, mathematics, and other academic skills and that there are genetic influences on this normal variation, even independent of genetic influences on IQ.3 T h e third premise, although likely, is a separate question. Conceivably, only subclinical (suprathreshold) variation could be genetically influenced, with all subthreshold cases due to environmental causes, both biologic and social. Thus, although we can almost derive logically the fact of genetic influences on LDs from what we already know about the behavior genetics of normal variation in academic skills, we still need direct evidence. i h e r e are two main strategies for obtaining this direct evidence. One is to begin with the phenotype and work backward to the genotype; the other is to begin with a known genotype and examine whether its phenotype includes a specific LD."5 Both strategies have been fruitful and have yielded direct evidence of genetic influences on LDs. In what follows, we will review results coming from each strategy and then conclude with a section on clinical implications.
Professor of Psychology, Psychology Department, University o f Denver, Denver, Colorado Reprint requests: Dr. Pennington, Psychology Department, University of Denver, Denver,
