Jeannette Locke

Factors predicting the onset of adolescent drinking in families at high risk for developing alcoholism

BACKGROUND With a longitudinal prospective design, the purpose of this study was 1) to assess, with survival analysis, the age of onset of drinking in relation to family history of alcoholism; 2) to examine the importance of selected neurobiological and psychosocial risk factors in predicting the onset to drink; and 3) to determine if the age of onset of substance dependence problems differed by risk group status. METHODS One hundred twenty-five children and adolescents were evaluated annually (N = 638 evaluations), providing up to seven annual waves of longitudinal data. Survival analyses were performed to determine the age of onset of regular drinking and the age of onset for substance abuse/dependence. The age of onset of regular drinking outcome was modeled using familial density of alcoholism and four factors, which included neurobiological indices of development (postural sway and P300), personality characteristics, academic achievement, self-esteem, and trait anxiety. RESULTS High-risk children/adolescents showed a significantly earlier age of onset of drinking and an earlier age of onset for substance abuse problems. Familial density of alcoholism predicted an earlier onset of drinking, as did having deficits in reading achievement, reduced P300 (visual and auditory), and greater postural sway for age. Higher scores on the Extraversion scale of the Junior version of the Eysenck Personality Inventory also predicted an earlier onset of drinking. CONCLUSIONS Familial density of alcoholism (number of alcoholic first- and second-degree relatives) is an important predictor of adolescent alcohol initiation. Evidence is presented suggesting that part of the familial/genetic variation in outcome may be due to neurobiological factors and temperament.

Developmental delay in P300 production in children at high risk for developing alcohol-related disorders.

BACKGROUND Reduction of P300 amplitude in children and adolescents at high risk for developing alcoholism has frequently been reported. It has been hypothesized that this reduction represents a developmental delay in reaching age-appropriate levels in P300 amplitude. Using latent growth analysis of longitudinal data obtained at yearly intervals, this study seeks to define normal growth, and determine if the pattern seen in high-risk children differs from that obtained in normal low-risk controls. METHODS A total of 156 children from either high or low-risk families have been assessed multiple times (two-thirds more than 4 times) using both a clinical assessment (K-SADS) and ERP evaluation performed on the same day. A total of 635 separate assessments were available for modeling. RESULTS Quadratic growth curves revealed a slower rate of change in P300 amplitude in high-risk than low-risk males. High-risk girls showed reduced visual P300 amplitude only when the presence of a K-SADS diagnosis was considered. No differences were seen for P300 latency. CONCLUSIONS This study confirms the hypothesis that when reduction of P300 amplitude is seen in males at high risk for developing alcoholism, it is due to a developmental delay.

Genetic association between reduced P300 amplitude and the DRD2 dopamine receptor A1 allele in children at high risk for alcoholism

BACKGROUND There is evidence that both reduction in P300 amplitude and the presence of the A1 allele are risk markers for alcoholism. We hypothesized that demonstration of a relationship between the marker and the trait in young children who had not begun to drink regularly would provide evidence for dopaminergic mediation of the reduction in P300 often seen among high-risk children. A previous association between the A1 and the P300 amplitude in screened controls supports the hypothesis that this association occurs in the general population. METHODS Children were assessed using both visual and auditory paradigms to elicit event-related potentials (ERPs). The P300 component of the ERP was investigated with respect to the genetic variation of the Taq1A D2 receptor in these children. RESULTS Genetic association between a marker locus (Taq1 A RFLP near the D2 receptor locus) and the amplitude of P300 was found to be present in 58 high-risk children and their relatives (a total of 100 high-risk individuals). CONCLUSIONS A higher proportion of children from alcoholic families may exhibit lower P300 because more of these children carry the A1 allele than is seen in the normal population.

P300 amplitude decrements in children from families of alcoholic female probands.

A total of 70 age- and gender-matched children and their relatives who were from families that were either at high or low risk for developing alcoholism were studied and the children evaluated using event-related potential paradigms from both the auditory and visual modalities. The high-risk children were ascertained through families at exceptionally high risk for female alcoholism (half of all female first- and second-degree relatives were alcoholic), while low-risk control families had been selected for absence of alcoholism in first- and second-degree relatives. Results indicate that reduced amplitude of P300 and greater negativity of N250 characterize children from high-risk families when evaluated with an auditory task. The visual task discriminated high- and low-risk groups for male children only, consistent with earlier findings for high-risk families ascertained through a male alcoholic. Further, daughters of alcoholic mothers (biological father nonalcoholic) display significantly lower P300 than matched controls, indicating that transmission of alcoholism risk may be possible from mother to daughter without the necessity of paternal alcoholism.

Personality traits and dopamine receptors (D2 and D4): linkage studies in families of alcoholics.

Activation of the mesolimbic dopamine pathway appears to promote drug- and alcohol-seeking behavior in laboratory animals. Results for association and linkage analysis between various alcohol dependence phenotypes and the dopamine receptors have been quite mixed. Similarly, both positive and negative results have been presented concerning dopamine receptor genes and temperament. Cloninger has postulated that the novelty seeking factor from the Tridimensional Personality Questionnaire (TPQ) may be related to the dopamine neurotransmitter system. As novelty seeking is a trait of some importance for substance-dependent individuals, our goal was to test this relationship within a sample of families of alcoholics. No evidence favoring linkage between D2, D4, or DAT1 was found for TPQ novelty seeking. However, the harm-avoidance trait from the TPQ showed evidence for linkage to both the D4 and one of the D2 loci (TaqI A). The Multidimensional Personality Questionnaire (MPQ) was used to provide converging evidence for these results. The TPQ harm-avoidance scale loads heavily on introversion (worry, pessimism, shyness), characteristics that may be especially salient in alcoholic families. Thus, planned comparisons were made between selected MPQ traits measuring the affective dimension (negative affectivity, stress reaction, alienation, and well-being). We find evidence favoring linkage between the D2 and D4 receptor loci and these MPQ traits, with stronger evidence being seen for the D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:634-641, 1999.

Psychopathology and Achievement in Children at High Risk for Developing Alcoholism

OBJECTIVE To compare rates of psychopathology and academic achievement in children who were either at high or low risk for developing alcoholism and to determine whether academic deficits would predict prospectively the presence of psychopathology occurring within the next year. METHOD Children and adolescents, aged 8 to 18 years, were evaluated as part of a longitudinal follow-up. Diagnoses obtained by using the Schedule for Affective Disorders and Schizophrenia for School-Age Children and grade-equivalent scores from the reading, spelling, and arithmetic sections of the Wide Range Achievement Test were determined at yearly intervals. RESULTS High-risk offspring were more likely to have a diagnosable disorder. In addition, analyses using the mothers and fathers diagnosis of alcoholism as a covariate showed higher hazard ratios for selected disorders (depression, affective disorder, attention-deficit/hyperactivity disorder, and conduct disorder), some of which were gender-dependent. Logistic regression analysis of achievement test scores demonstrated that reading and math scores predicted the presence of childhood psychopathology at the following annual evaluation. CONCLUSIONS Children from pedigrees with a high density of alcoholism are at greater risk for developing psychopathology. Furthermore, observed deficits in academic performance may be considered an indicator of a developing diagnosable illness.

Absence of visual and auditory P300 reduction in nondepressed male and female alcoholics

BACKGROUND The P300 component of the event-related potential has been extensively studied as a possible neurobiological risk marker for the development of alcoholism. Although P300 amplitude reduction has frequently been documented in high-risk children, studies of adult alcoholics are inconsistent. METHODS P300 amplitude from 121 adult alcoholics was compared to 68 controls utilizing event-related potential paradigms from the auditory and visual modalities. All participants were evaluated clinically with psychiatric interviews and administered the MMPI. RESULTS Male alcoholics did not show a reduction in amplitude in either the auditory or visual modality. Female alcoholics showed reduced P300 amplitude, but only when a comorbid lifetime diagnosis of depression was present. Similar results were found using current depressed mood (Scale 2 from the MMPI). CONCLUSIONS No differences in P300 amplitude were found between alcoholics and controls unless comorbid depression was present. Therefore, P300 amplitude reduction seen in children at high-risk for developing alcoholism seems to represent a neurodevelopmental delay that normalizes by adulthood.

Path analysis of P300 amplitude of individuals from families at high and low risk for developing alcoholism.

BACKGROUND A substantial amount of evidence exists suggesting that P300 amplitude in childhood is a risk marker for later development of alcohol dependence. There is evidence that P300 amplitude is heritable. The goal of the present study was to determine if patterns of transmission differed in families who were either at high or low risk for developing alcohol dependence. METHODS Auditory P300 was recorded from 536 individuals spanning three generations. The path analytic TAU model was used to investigate the familial transmission of P300 amplitude in the two independent samples of families. RESULTS Transmission of P300 in high-risk families most likely followed a polygenic model of inheritance with significant parent-to-offspring transmission. Parent-to-offspring transmission was significantly greater in high-risk than low-risk families. Total phenotypic variance due to transmissible factors was greater in low-risk families than in high-risk families, however. A somewhat unexpected finding was the substantial correlation between mates for P300 amplitude in both high- and low-risk families. CONCLUSIONS P300 is transmissible in families. Differences exist in the pattern of transmission for P300 in families at high and low risk for alcoholism.

Developmental changes in postural sway in children at high and low risk for developing alcohol-related disorders.

BACKGROUND To utilize the power of latent growth analysis to evaluate changes in postural sway during development in children who are either at high or low risk for developing alcoholism. METHODS A total of 629 assessments of postural sway have been performed in children and adolescents (n = 126) who were evaluated annually over a 7-year period. RESULTS Latent curve models indicated that these children/adolescents show a linear decrease in sway with age. Moreover, significantly different rates of change in the amount of sway between high- and low-risk offspring were seen. With the exception of one of the four stances tested, high-risk boys consistently showed a slower rate of improvement with respect to the amount of sway exhibited compared to low-risk boys. In girls, similar rates of improvement with age were seen in high- and low-risk individuals, though in one stance the high-risk girls showed a deterioration (greater sway with increasing age). CONCLUSIONS Previous reports of increased postural sway in high-risk offspring most likely reflect a developmental delay (high-risk children have greater sway than is appropriate for their age based on normative values by age).

Risk markers for alcoholism in high-density families

This review summarizes the efforts of our research program to identify markers for alcoholism risk, which broadly fall within the domain of temperament and those which may be described as attentional or information-processing capacities. Analyses of three-generation pedigrees that include minor children at higher risk of becoming alcoholic indicate that event-related potential characteristics differ between high- and low-risk children. Newer results concerning cardiac responsivity both in minor children and adult high-risk individuals are presented. These results suggest a relationship between personality or temperament on the one hand, and cardiac responsivity on the other. Additional neurobehavioral markers are addressed including static ataxia. Recent segregation analyses and linkage to particular DNA segments are also included.