A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory : Multiple candidate genes

Human genetics is now at a critical juncture. The molecular methods used successfully to identify the genes underlying rare mendelian syndromes are failing to find the numerous genes causing more common, familial, non-mendelian diseases. With the human genome sequence nearing completion, new opportunities are being presented for unravelling the complex genetic basis of non-mendelian disorders based on large-scale genome-wide studies. Considerable debate has arisen regarding the best approach to take. In this review I discuss these issues, together with suggestions for optimal post-genome strategies.

Clinical, genetic, and neuropsychopharmacological studies of developmental factors in alcoholism are providing a better understanding of the neurobiological bases of personality and learning. Studies of the adopted-away children of alcoholics show that the predisposition to initiate alcohol-seeking behavior is genetically different from susceptibility to loss of control after drinking begins. Alcohol-seeking behavior is a special case of exploratory appetitive behavior and involves different neurogenetic processes than do susceptibility to behavioral tolerance and dependence on the antianxiety or sedative effects of alcohol. Three dimensions of personality have been described that may reflect individual differences in brain systems modulating the activation, maintenance, and inhibition of behavioral responses to the effects of alcohol and other environmental stimuli. These personality traits distinguish alcoholics with different patterns of behavioral, neurophysiological, and neuropharmacological responses to alcohol.

Recently, attention has focused on the use of whole-genome linkage disequilibrium (LD) studies to map common disease genes. Such studies would employ a dense map of single nucleotide polymorphisms (SNPs) to detect association between a marker and disease. Construction of SNP maps is currently underway. An essential issue yet to be settled is the required marker density of such maps. Here, I use population simulations to estimate the extent of LD surrounding common gene variants in the general human population as well as in isolated populations. Two main conclusions emerge from these investigations. First, a useful level of LD is unlikely to extend beyond an average distance of roughly 3 kb in the general population, which implies that approximately 500,000 SNPs will be required for whole-genome studies. Second, the extent of LD is similar in isolated populations unless the founding bottleneck is very narrow or the frequency of the variant is low (<5%).