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Alysa E Doyle

Publications and source records attributed to Alysa E Doyle.

At least 19 recordsLinked to original sources
PubMed2026

Can Psychiatric Genetics Advance Without Incorporating a Life Course Perspective?

Psychiatric disorders unfold over the life course; however, genomic studies of these conditions overwhelmingly rely on phenotypes collected at a single time point, often in adulthood. Therefore, genome-wide association studies (GWASs) of psychiatric conditions may miss genetic variants with time-varying relevance to etiology, prevention, and treatment, such as those that influence trajectories of symptoms and behaviors, age at onset, course of treatment response, and the co-evolution of comorbidities. With recent advances in longitudinal biobanks and analytic tools, we posit that incorporating a life course perspective in psychiatric genetics will enable critically relevant insights into each of these areas of investigation. We propose that the current inconsistent portability of polygenic scores across age groups can be reconciled through the design of carefully considered longitudinal GWASs in age-diverse samples. Pioneering longitudinal GWASs in psychiatry have revealed novel genomic signals associated with time-dependent phenotypes that are distinct from those influencing lifetime diagnosis, suggesting that the study of longitudinal phenotypes will complement cross-sectional approaches and empower biological and therapeutic discoveries. Advances in post-GWAS functional annotation resources and analytic approaches now enable us to contextualize the genetic contributions to psychiatric disorders as dynamic age- and exposure-dependent processes. Although longitudinal GWASs pose unique challenges with regard to data availability, selection bias, and missing data, integrating temporality into psychiatric genetics at scale is now attainable and promises to reveal novel biology and therapeutic opportunities for psychiatric conditions.

Cohort study↗
PubMed2006

Association between DRD4 gene and performance of children with ADHD in a test of sustained attention.

BACKGROUND: The adoption of neuropsychological tests as endophenotypic measures can provide an increased sensitivity to specific dimensions of attention-deficit/hyperactivity disorder (ADHD). METHODS: The association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children and adolescents with ADHD in a continuous performance test (CPT) was evaluated. The sample comprised 90 clinically referred children and adolescents with ADHD. Errors of omission and commission in the CPT were computed and the number of 48-base pairs tandem repeats in the exon III of DRD4 was assessed. RESULTS: The presence of a 7-repeat allele was associated with more errors of commission and the homozygosity of the 4-repeat allele was related to fewer errors of commission and omission even after adjusting for age. CONCLUSIONS: These findings bring further evidence on the role of DRD4 polymorphisms on the performance in sustained attention tasks among children and adolescents with ADHD diagnosis.

Adolescent↗
PubMed2006

Family based association analysis of statistically derived quantitative traits for drug use in ADHD and the dopamine transporter gene.

OBJECTIVE: To determine whether SNPs within the dopamine transporter gene (DAT) are associated with quantitative phenotypes generated from drug frequency variables in an ADHD sample. METHOD: 35 SNPs were genotyped in and around DAT. We developed a quantitative phenotype at each SNP by weighting the drug frequency variables. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, a screening procedure was used to select and test the SNPs with the greatest power to detect an association in DAT. RESULTS: No SNPs in DAT were associated with the quantitative phenotypes generated from the drug frequency variables after the multiple comparisons adjustment; however, some SNPs achieved nominal significance. A sliding window of analysis of 3 SNPs also resulted in only nominal associations. CONCLUSIONS: SNPs in DAT do not appear to be associated with the phenotypes generated from drug frequency variables among individuals with ADHD.

Adolescent↗
PubMed2006

Neuropsychological functioning in girls with attention-deficit/hyperactivity disorder with and without learning disabilities.

The authors' goal was to assess neuropsychological performance in girls with attention-deficit/hyperactivity disorder (ADHD) and evaluate the role of comorbid learning disabilities (LDs). Participants were 140 girls with ADHD and 122 girls without ADHD, ages 6-17 years. Neuropsychological performance was measured in a standardized manner, blind to clinical status. LD was defined by a combined regression-based and low-achievement classification. ADHD was associated with modest, but significant, neuropsychological impairment, as measured with an aggregate measure of performance and with the Stroop Color-Word Test, independent of age, social class, IQ, and psychiatric comorbidity. Neuropsychological deficits were most pronounced in girls with both ADHD and an LD and in those without medications. These results extend to females the previously documented association of LDs with neuropsychological functioning in males with ADHD.

Adolescent↗
PubMed2006

Impact of psychometrically defined deficits of executive functioning in adults with attention deficit hyperactivity disorder.

OBJECTIVE: The association between deficits in executive functioning and functional outcomes was examined among adults with attention deficit hyperactivity disorder (ADHD). METHOD: Subjects were adults who did (N=213) and did not (N=145) meet DSM-IV criteria for ADHD. The authors defined having deficits in executive functioning as having at least two measures of executive functioning with scores 1.5 standard deviations below those of matched comparison subjects. RESULTS: Significantly more adults with ADHD had deficits of executive functioning than comparison subjects. Deficits of executive functioning were associated with lower academic achievement, irrespective of ADHD status. Subjects with ADHD with deficits of executive functioning had a significantly lower socioeconomic status and a significant functional morbidity beyond the diagnosis of ADHD alone. CONCLUSIONS: Psychometrically defined deficits of executive functioning may help identify a subgroup of adults with ADHD at high risk for occupational and academic underachievement. More efforts are needed to identify cost-effective approaches to screen individuals with ADHD for deficits of executive functioning.

Accidents, Traffic↗
PubMed2006

Executive functions in attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine the association between weaknesses in executive functions and attention-deficit/hyperactivity disorder (ADHD). METHOD: Empirical studies examining executive functions in ADHD samples were reviewed, with particular attention to results of recent meta-analyses. RESULTS: ADHD is associated with impaired performance on measures of response inhibition, working memory, and other aspects of executive functions, yet data also suggest significant neuropsychological variability within and across ADHD samples. CONCLUSION: ADHD may be best conceptualized as a neuropsychologically heterogeneous condition. More work is needed to characterize this heterogeneity and its clinical and pathophysiologic implications.

Attention↗
PubMed2005

Neuropsychological functioning in youth with bipolar disorder.

BACKGROUND: Little is known about the neuropsychological status of youth with bipolar disorder (BPD) or whether cognitive deficits in this population are accounted for by comorbidity with attention deficit/hyperactivity disorder (ADHD). We compared neuropsychological and academic functioning of youth with and without DSM-IV BPD, controlling for effects of comorbid ADHD. METHODS: Fifty-seven youth with BPD and 46 healthy control subjects were assessed on a battery of clinical neuropsychological measures including subtests from the Wechsler Intelligence Scales for Children and Adults (Third Editions), the Stroop, the Wisconsin Card Sorting Test, the Rey-Osterreith Complex Figure, an auditory working memory Continuous Performance Test, a measure of verbal learning, and the Wide Range Achievement Test-Third Edition. RESULTS: Bipolar disorder was associated with impairments on subtests reflecting sustained attention, working memory, and processing speed after controlling for ADHD. Additionally, decrements of moderate effect sizes were found for measures of interference control, abstract problem solving, and verbal learning but did not meet criteria for statistical significance. CONCLUSIONS: After controlling for ADHD, youth with BPD show neuropsychological deficits similar to impairments found in adults with the disorder. Further studies are needed to understand the clinical implications of these impairments as well as their role in the underlying risk for pediatric BPD.

Adolescent↗
PubMed2005

Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD.

BACKGROUND: Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported. METHODS: To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes. RESULTS: We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. CONCLUSIONS: These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.

Adolescent↗
PubMed2005

Causal heterogeneity in attention-deficit/hyperactivity disorder: do we need neuropsychologically impaired subtypes?

Before assigning full etiologic validity to a psycopathologic disorder, disease theory suggests that a causal dysfunction in a mechanism within the affect individuals must be identified. Existing theories on attention-deficit/hyperactivity disorder (ADHD) suggest such dysfunctions in cognitive, neuropsychological, or motivational processes in the child. To date, researchers have tested these theories by comparing groups with DSM-defined ADHD to children without ADHD. Using executive functioning as an illustration of an issue that exists across all such theories, this article describes substantial overlaps in the group performance data. Thus only a subgroup may have executive deficits. Noted are other supportive data suggesting multiple pathways to ADHD. The article explores implications and recommends that future theory and research give more consideration to the probability that only a subset of behaviorally defined children will have a deficit in a given neurocognitive mechanism believed to contribute to the disorder. Creation of a provisional set of criteria in DSM-V for defining an "executive deficit type" could stimulate research to validate the first etiologic subtype of ADHD and spur the development of more sophisticated causal models, which in the longer term may give clinicians ways to target and tailor treatments.

Attention Deficit Disorder with Hyperactivity↗
PubMed2005

Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review.

One of the most prominent neuropsychologic theories of attention-deficit/hyperactivity disorder (ADHD) suggests that its symptoms arise from a primary deficit in executive functions (EF), defined as neurocognitive processes that maintain an appropriate problem-solving set to attain a later goal. To examine the validity of the EF theory, we conducted a meta-analysis of 83 studies that administered EF measures to groups with ADHD (total N = 3734) and without ADHD (N = 2969). Groups with ADHD exhibited significant impairment on all EF tasks. Effect sizes for all measures fell in the medium range (.46-.69), but the strongest and most consistent effects were obtained on measures of response inhibition, vigilance, working memory, and planning. Weaknesses in EF were significant in both clinic-referred and community samples and were not explained by group differences in intelligence, academic achievement, or symptoms of other disorders. ADHD is associated with significant weaknesses in several key EF domains. However, moderate effect sizes and lack of universality of EF deficits among individuals with ADHD suggest that EF weaknesses are neither necessary nor sufficient to cause all cases of ADHD. Difficulties with EF appear to be one important component of the complex neuropsychology of ADHD.

Algorithms↗
PubMed2005

Attention-deficit/hyperactivity disorder endophenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.

Adoption↗
PubMed2005

Molecular genetics of attention-deficit/hyperactivity disorder.

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.

Adoption↗
PubMed2005

Neuropsychological functioning in relatives of girls with and without ADHD.

BACKGROUND: A limited number of studies have examined neuropsychological functioning in the family members of ADHD youth, and none have focused exclusively on relatives of females. METHOD: Structured diagnostic interviews and neuropsychological batteries were administered to parents and siblings enrolled in a family study of girls with and without ADHD. Relatives were stratified into three groups: relatives of DSM-IV ADHD probands with ADHD (n = 106), relatives of ADHD probands without ADHD (n = 189) and relatives of controls without ADHD (n = 243). Analyses were also conducted on a subgroup of families in which more than one member had RESULTS: The neuropsychological battery as a whole distinguished affected and unaffected ADHD relatives from controls. The Wechsler Oral Arithmetic subtest, the Stroop Word, Color and Color-Word subscales were impaired in affected ADHD relatives, as were the WRAT-R Arithmetic and Reading subtests. Only the Stroop Color-Word and Interference subtests and the WRAT-R Arithmetic subtest showed significant impairments in unaffected relatives. In multiplex families, additional impairments were found in unaffected relatives on the Stroop Color subtest and the Wechsler Oral Arithmetic subtest. Analyses based on DSM-III-R diagnoses produced nearly identical results. Minor differences emerged across relatives of probands with different DSM-IV subtypes. CONCLUSIONS: Data were consistent with our previous study of relatives of boys with ADHD. Neuropsychological impairments in relatives of female ADHD probands were primarily associated with the diagnosis of ADHD, but subtle cognitive impairments that index familial vulnerability to the disorder may exist.

Adolescent↗
PubMed2005

Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD?

BACKGROUND: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or phenotypes that are more closely linked to the neurobiological substrate of a disorder, offer the potential to address these two issues simultaneously (Freedman, Adler, & Leonard, 1999). Thus far, potential endophenotypes for ADHD have not been systematically studied. METHOD: The current paper reviews evidence supporting the use of deficits on neurocognitive measures of executive functions for this purpose. RESULTS: Such deficits are a correlate of ADHD and show preliminary evidence of heritability and association with relevant candidate genes. Nonetheless, studies that have assessed the familial and genetic overlap of neurocognitive impairments with ADHD have yielded inconsistent results. CONCLUSIONS: In order for executive function deficits to be used as an endophenotype for ADHD, we recommend greater attention to the neurocognitive heterogeneity of this disorder and to the precision of measurement of the neuropsychological tests employed. We also discuss empirical strategies that may be necessary to allow such research to progress prior to full resolution of the pathophysiological basis of ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed2005

Impact of gender and age on executive functioning: do girls and boys with and without attention deficit hyperactivity disorder differ neuropsychologically in preteen and teenage years?

ADHD is known to have neuropsychological correlates, characterized mainly by executive function (EF) deficits. However, most available data are based on studies of boys through age 12. Our goal was to assess whether girls with ADHD express neuropsychological features similar to those found in boys, and whether these impairments are found in both preteen and teen samples. Participants were 101 girls and 103 boys with DSM-III-R ADHD, and 109 comparison girls and 70 boys without ADHD, ages 9 to 17 years. Information on neuropsychological performance was obtained in a standardized manner blind to clinical status. Primary regression analyses controlled for age, socioeconomic status, learning disability, and psychiatric comorbidity. Girls and boys with ADHD were significantly more impaired on some measures of EFs than healthy comparisons but did not differ significantly from each other. With the exception of 1 test score there were no significant Sex x Diagnosis interactions. Moreover, there were no more significant interactions among age, gender, and diagnosis than would be expected by chance. Neuropsychological measures of EFs were comparably impaired in girls compared to boys with ADHD, and these impairments are found at ages 9 to 12 and ages 13 to 17. These findings suggest that executive dysfunctions are correlates of ADHD regardless of gender and age, at least through the late teen years.

Adolescent↗
PubMed2004

Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children.

The association between executive function deficits (EFDs) and functional outcomes were examined among children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Participants were children and adolescents with (n = 259) and without (n = 222) ADHD, as ascertained from pediatric and psychiatric clinics. The authors defined EFD as at least 2 executive function measures impaired. Significantly more children and adolescents with ADHD had EFDs than did control participants. ADHD with EFDs was associated with an increased risk for grade retention and a decrease in academic achievement relative to (a) ADHD alone, (b) controlled socioeconomic status, (c) learning disabilities, and (d) IQ. No differences were noted in social functioning or psychiatric comorbidity. Children and adolescents with ADHD and EFDs were found to be at high risk for significant impairments in academic functioning. These results support screening children with ADHD for EFDs to prevent academic failure.

Achievement↗
PubMed2003

Diagnostic threshold for conduct disorder in girls and boys.

Concerns about gender bias in the diagnostic criteria for conduct disorder (CD) have prompted some researchers to recommend that the diagnostic threshold in girls be lowered. Since CD is a highly familial condition, the authors assessed the diagnostic validity of subthreshold CD in girls using family study methodology. They compared the rates of antisocial disorders (CD and antisocial personality disorder) in relatives of four groups of index children: children with attention deficit hyperactivity disorder (ADHD) and full, subthreshold, or no CD diagnoses and non-ADHD/non-CD control subjects. Results showed no interaction between gender and familiality across the four groups. Furthermore, there was no significant evidence of familiality of subthreshold CD. From a family genetic perspective, the diagnostic threshold for CD does not appear to differ by gender. The current results support the possibility that differential rates of CD reflect actual differences in rates of antisocial behavior across gender.

Antisocial Personality Disorder↗