Understanding comorbidity: a twin study of reading disability and attention-deficit/hyperactivity disorder.

A community sample of twins in which at least one member of each pair exhibited significant reading difficulties (99 monozygotic and 80 dizygotic pairs) or symptoms of attention-deficit/hyperactivity disorder (ADHD; 83 monozygotic and 78 dizygotic pairs) was used to test the etiology of comorbidity between reading disability (RD) and ADHD. Univariate analyses revealed moderate to high heritability for all measures of reading difficulty and ADHD. Subsequent bivariate analyses indicated that the relation between reading difficulties and inattention symptoms is primarily attributable to common genetic influences, whereas bivariate heritability estimates were not significant for hyperactivity-impulsivity and any of the reading measures. Reading difficulties and ADHD symptoms were more highly heritable if the proband met criteria for both disorders versus RD or ADHD alone, suggesting that future molecular genetic analyses of comorbid RD + ADHD may facilitate the identification of susceptibility genes for RD, ADHD, and their comorbidity.     

Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non-affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD = 2.93), 13q22.2 (LOD = 2.36), and 17p13.3 (LOD = 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used.     

A pilot twin study of psychological measures of attention deficit hyperactivity disorder

There has been much interest in the genetics of attention deficit hyperactivity disorder and molecular genetic studies are now underway. The success of genetic studies will depend on how well the phenotype is defined. Twin studies using parent and teacher rated questionnaires or interviews all appear to yield highly heritable measures. Nevertheless, there is evidence to suggest that parent measures are subject to rater bias. Consequently there has been much interest in obtaining more objective measures of related traits such as attention span and impulsiveness using, computerised neuropsychological tasks. However there have been few twin studies examining the genetic contribution to these neuropsychological measures. The present study aims to investigate whether performance on the Matching Familiar Figures Test (MFFT) and Continuous Performance Task (CPT) is genetically influenced in childhood. 20 monozygotic (MZ) and 20 dizygotic (DZ) twin pairs were randomly selected from the Greater Manchester Twin Register. Preliminary data suggest that MZ twins perform more similarly than DZ twins on the MFFT, but not the CPT. Future work needs to examine whether other neuropsychological measures commonly used in research on ADHD are genetically influenced using larger twin samples.     

Speed,Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research?

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD. Edited by Irwin Waldman.     

Heritability of cognitive functions in families with bipolar disorder.

Bipolar disorder is highly heritable. Cognitive dysfunctions often observed in bipolar patients and their unaffected relatives implicate that these impairments may be associated with genetic predisposition to bipolar disorder and thus fulfill the criteria of a valid endophenotype for the disorder. However, the most fundamental criterion, their heritability, has not been directly studied in any bipolar population. This population-based study estimated the heritability of cognitive functions in bipolar disorder. A comprehensive neuropsychological test battery and the Structured Clinical Interview for DSM-IV were administered to a population-based sample of 110 individuals from 52 families with bipolar disorder. Heritability of cognitive functions as assessed with neuropsychological test scores were estimated using the Solar package. Significant additive heritabilities were found in verbal ability, executive functioning, and psychomotor processing speed. Genetic contribution was low to verbal learning functions. High heritability, in executive functioning and psychomotor processing speed suggest that these may be valid endophenotypic traits for genetic studies of bipolar disorder.     

Adjudicating neurocognitive endophenotypes for schizophrenia.

Although genetic influences on schizophrenia are well established, localization of the genes responsible for this illness has proven extremely difficult. Given evidence that genes predisposing to schizophrenia may be transmitted without expression of the clinical phenotype, efforts have focused on developing endophenotypes. While several neuropsychological measures have been proposed to be endophenotypes, few studies have systematically assessed batteries of neurocognitive tests to determine which tests are most sensitive to liability for the illness. Two hundred sixty-nine Latino individuals were administered a standard neuropsychological battery. Two hundred fourteen of these were members of families with at least two siblings diagnosed with schizophrenia or schizoaffective disorder. The remaining were community controls without history of major psychiatric illness. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests covary with the degree of genetic relationship to affected individuals. Although five measures were found to uniquely model genetic liability for schizophrenia, digit symbol coding was the most sensitive. To assess the specificity of these endophenotypes, performance on these measures were compared to family members with bipolar and unipolar affective disorders. These markers clearly distinguished between individuals with psychotic illnesses and those with major depression. As measures contributed uniquely to discriminate individuals at varying risk for schizophrenia, our findings imply multiple independently inherited elements to the liability for the illness. We present a practical model for adjudicating endophenotypes and determining which measures are best suited for use in linkage analyses.     

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 × 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.     

Heritability of brain volumes in older adults: the Older Australian Twins Study

The relative contributions of genetic and environmental factors to brain structure change throughout the lifespan. Brain structures have been reported to be highly heritable in middle-aged individuals and younger; however, the influence of genes on brain structure is less studied in older adults. We performed a magnetic resonance imaging study of 236 older twins, with a mean age of 71.4 ± 5.7 years, to examine the heritability of 53 brain global and lobar volumetric measures. Total brain volume (63%) and other volumetric measures were moderately to highly heritable in late life, and these genetic influences tended to decrease with age, suggesting a greater influence of environmental factors as age advanced. Genetic influences were higher in men and on the left hemisphere compared with the right. In multivariate models, common genetic factors were observed for global and lobar total and gray matter volumes. This study examined the genetic contribution to 53 brain global and lobar volumetric measures in older twins for the first time, and the influence of age, sex, and laterality on these genetic contributions, which are useful information for a better understanding of the process of brain aging and helping individuals to have a healthy aging.     

ADHD: sibling interaction or dominance: an evaluation of statistical power

Sibling interaction effects are suggested by a difference in phenotypic variance between mono-zygotic (MZ) twins and dizygotic (DZ) twins, and a pattern of twin correlations that is inconsistent with additive genetic influences. Notably, negative sibling interaction will result in MZ correlations which are more than twice as high as DZ correlations, a pattern also seen in the presence of genetic dominance. Negative sibling interaction effects have been reported in most genetic studies on Attention Deficit Hyperactivity Disorder (ADHD) and related phenotypes, while the presence of genetic dominance is not always considered in these studies. In the present paper the statistical power to detect both negative sibling interaction effects and genetic dominance is explored. Power calculations are presented for univariate models including sources of variation due to additive genetic influences, unique environmental influences, dominant genetic influences and a negative sibling interaction (i.e., contrast effect) between phenotypes of twins. Parameter values for heritability and contrast effects are chosen in accordance with published behavior genetic studies on ADHD and associated phenotypes. Results show that when both genetic dominance and contrast effects are truly present and using a classical twin design, genetic dominance is more likely to go undetected than the contrast effect. Failure to detect the presence of genetic dominance consequently gives rise to slightly biased estimates of additive genetic effects, unique environmental effects, and the contrast effect. Contrast effects are more easily detected in the absence of genetic dominance. If the significance of the contrast effect is evaluated while also including genetic dominance, small contrast effects are likely to go undetected, resulting in a relatively large bias in estimates of the other parameters. Alternative genetic designs, such as adding pairs of unrelated siblings reared together to a classical twin design, or adding non-twin siblings to twin pairs, greatly enhances the statistical power to detect contrast effects as well as the power to distinguish between genetic dominance and contrast effects.     

Heritability of levels of autoantibodies to thyroid antigens using the method of plotting regression of offspring on midparent (ROMP)

Only a few methods can be applied in a simple manner to estimate the genetic control of autoimmunity in humans. Here we examined the heritability of autoantibodies to two thyroid antigens; thyroglobulin (Tg) and thyroperoxidase (TPO, formerly known as thyroid microsomal antigen), using methods of regression of offspring on mid-parental values (ROMP). With the data sets available, affected and unaffected siblings were compared by this rapid screening method using results determined by hemagglutination (HA). The presence of both types of autoantibodies showed positive heritability in patients with Graves' thyrotoxicosis (TT), but it was not observed in chronic lymphocytic or Hashimoto's thyroiditis (CLT) patients. Since these assays have been extensively used over the years by most diagnostic and research laboratories, they should provide some insight as to which quantifiable parameters may be usefully accumulated to help select groups of patients and their families for further genetic study. ROMP may also be useful to determine the sequential appearance of different types of antibody in predicting disease onset in other family members, and in distinguishing maternal and paternal effects on imprinting. The method may be extended to study epitope spreading and other measures of disease progression.     

Heritability of levels of autoantibodies to thyroid antigens using the method of plotting regression of offspring on midparent (ROMP)

Only a few methods can be applied in a simple manner to estimate the genetic control of autoimmunity in humans. Here we examined the heritability of autoantibodies to two thyroid antigens; thyroglobulin (Tg) and thyroperoxidase (TPO, formerly known as thyroid microsomal antigen), using methods of regression of offspring on mid-parental values (ROMP). With the data sets available, affected and unaffected siblings were compared by this rapid screening method using results determined by hemagglutination (HA). The presence of both types of autoantibodies showed positive heritability in patients with Graves' thyrotoxicosis (TT), but it was not observed in chronic lymphocytic or Hashimoto's thyroiditis (CLT) patients. Since these assays have been extensively used over the years by most diagnostic and research laboratories, they should provide some insight as to which quantifiable parameters may be usefully accumulated to help select groups of patients and their families for further genetic study. ROMP may also be useful to determine the sequential appearance of different types of antibody in predicting disease onset in other family members, and in distinguishing maternal and paternal effects on imprinting. The method may be extended to study epitope spreading and other measures of disease progression.     

Borderline personality traits and adult attention‐deficit hyperactivity disorder symptoms: A genetic analysis of comorbidity

Previous research has established the comorbidity of adult Attention‐Deficit Hyperactivity Disorder (ADHD) with different personality disorders including Borderline Personality Disorder (BPD). The association between adult ADHD and BPD has primarily been investigated at the phenotypic level and not yet at the genetic level. The present study investigates the genetic and environmental contributions to the association between borderline personality traits (BPT) and ADHD symptoms in a sample of 7,233 twins and siblings (aged 18–90 years) registered with the Netherlands Twin Register and the East Flanders Prospective Twin Survey (EFPTS) . Participants completed the Conners' Adult ADHD Rating Scales (CAARS‐S:SV) and the Personality Assessment Inventory‐Borderline Features Scale (PAI‐BOR). A bivariate genetic analysis was performed to determine the extent to which genetic and environmental factors influence variation in BPT and ADHD symptoms and the covariance between them. The heritability of BPT and ADHD symptoms was estimated at 45 and 36%, respectively. The remaining variance in BPT and ADHD symptoms was explained by unique environmental influences. The phenotypic correlation between BPT and ADHD symptoms was estimated at r = 0.59, and could be explained for 49% by genetic factors and 51% by environmental factors. The genetic and environmental correlations between BPT and ADHD symptoms were 0.72 and 0.51, respectively. The shared etiology between BPT and ADHD symptoms is thus a likely cause for the comorbidity of the two disorders. © 2011 Wiley‐Liss, Inc.     

Genes of Experience: Explaining the Heritability of Putative Environmental Variables Through Their Association with Behavioural and Emotional Traits

An increasing body of evidence shows that many ‘environmental’ measures are heritable, indicating genetic involvement in environmental exposure (or gene–environment correlation). In the present study we attempt to clarify why three such ‘environmental’ measures (maternal negativity, paternal negativity and negative life events) are consistently found to be heritable. Through multivariate genetic analysis of a sample of adolescent twins from the UK we show that the heritability of these putative environmental measures can be explained via their association with five behavioural phenotypes: oppositionality, delinquency, physical aggression, depression and anxiety. This is consistent with the notion that being genetically susceptible to certain behavioural difficulties could lead to exposure to certain life events, and this may account for the reported heritability of ‘environmental’ measures. Results are discussed in the context of possible active, evocative and passive gene–environment correlations.     

Etiology of Reading Difficulties and Rapid Naming: The Colorado Twin Study of Reading Disability

Children with reading deficits perform more slowly than normally-achieving readers on speed of processing measures, such as rapid naming (RN). Although rapid naming is a well-established correlate of reading performance and both are heritable, few studies have attempted to assess the cause of their covariation. Measures of rapid naming (numbers, colors, objects, and letters subtests), phonological decoding, orthographic choice, and a composite variable (DISCR) derived from the reading recognition, reading comprehension, and spelling subtests of the Peabody Individual Achievement Test were obtained from a total of 550 twin pairs with a positive school history of reading problems. Basic DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data confirmed the heritable nature of phonological decoding, orthographic choice, DISCR, and rapid-naming composites. Bivariate DF models were employed to examine the extent to which deficits in the three reading-related measures covary genetically with rapid naming. Significant bivariate heritability estimates for each of the reading measures with the numbers and letters rapid-naming composite were also obtained. As expected, univariate sib-pair linkage analyses indicated the presence of a quantitative trait locus (QTL) on chromosome 6p21.3 for phonological decoding and orthographic choice deficits. Bivariate linkage analyses were then conducted to test the hypothesis that this QTL for reading difficulties is pleiotropic for slower performance on RN tasks. The results obtained from these analyses did not provide substantial evidence that the 6p QTL for reading difficulties has significant effects on rapid naming; however, larger samples would be required to test this hypothesis more rigorously.     

DeFries–Fulker Analysis of Longitudinal Reading Performance Data from Twin Pairs Ascertained for Reading Difficulties and from Their Nontwin Siblings

Reading difficulties are both heritable and stable; however, little is known about the etiology of this stability. Results from a preliminary analysis of data from 56 twin pairs who participated in the Colorado Longitudinal Twin Study of Reading Disability (Astrom et al., Twin Res Hum Genet 10:434–439, 2007) suggested that about two-thirds of the proband deficit at follow-up was due to genetic factors that also influenced deficits at their initial assessment. Although our proband sample is now nearly twice as large, it is still relatively small; thus, to increase power, we subjected data from probands, co-twins and their nontwin siblings to a novel extension of DeFries–Fulker analysis (DeFries and Fulker, Behav Genet 15:467–473, 1985; DeFries and Fulker, Acta Genet Med Gemellol, 37, 205–216, 1988). In addition to providing estimates of univariate and bivariate heritability, this analysis facilitates a test of the difference between shared environmental influences for twins versus siblings. Longitudinal composite reading performance scores at 10.6 and 15.5 years of age, on average, were analyzed from 33 MZ and 64 DZ twin pairs in which at least one member of each pair had reading difficulties, and from 44 siblings of the probands. Scores were highly stable (.86 ± .03, across probands, co-twins and siblings) and heritability of the group deficit at initial assessment was .67 ± .22. Longitudinal bivariate heritability was .59 ± .21, suggesting that nearly 60% of the proband reading deficit at follow-up is due to genetic factors that influenced reading difficulties at the initial assessment. However, tests for special twin environmental influences were nonsignificant.     

Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient

Recent genetic investigations of autism have studied multiplex families, typically including families with multiple siblings who meet criteria for a diagnosis of autism. However, little is known about the specific behavioral characteristics of siblings with autism in these multiplex families. We investigated the behavioral phenotypic variability and similarity of 351 siblings with autism in 171 multiplex families using cluster analysis and correlations. The results of cluster analyses showed that the individuals with autism could be characterized on a severity gradient: a continuum based on severity of symptoms and impairment as measured by Autism Diagnostic Interview-Revised (ADI-R) scores, verbal-nonverbal status, and nonverbal IQ scores. Clusters based on scores from the ADI-R for the autism diagnostic criteria of the DSM-IV and nonverbal IQ scores still represented a severity gradient when the effects of verbal-nonverbal status were removed. The severity gradient was shown to be heritable, with a sib correlation of 30% or a heritability of 60%. In summary, in a sample of 171 autism multiplex families, there was no evidence of discrete behaviorally defined subgroups of affected individuals or families characterized by distinct patterns of behavioral symptoms. Rather, the clusters could be characterized along a single, heritable, continuous severity dimension.     

Neuropsychological performance deficits in adults with attention deficit/hyperactivity disorder.

Neuropsychological deficits in children diagnosed with attention deficit/hyperactivity disorder (ADHD) have been well documented utilizing various neuropsychological tests. Only recently has research begun to examine if similar deficits are present in adults with ADHD. A neuropsychological testing battery was constructed that assessed verbal learning and memory, psychomotor speed, and sustained attention--all demonstrated to be deficient in individuals with ADHD. Fifty-six self-referred nonmedicated adults with a DSM-IV diagnosis of ADHD and 38 normal comparison adults participated. ADHD adults demonstrated verbal and nonverbal memory deficits and decreased psychomotor speed compared to normal controls. Differences between ADHD and normal adults were not documented on traditional measures of executive functioning. A pattern of results emerged whereby ADHD adults' performance, particularly with regard to psychomotor speed, became more impaired as task complexity increased. This study's results largely corroborate similar neuropsychological testing results in ADHD children and recent ADHD adult findings, and support a frontal lobe dysfunction hypothesis of ADHD.     

Heritability of substance dependence in a native American population

OBJECTIVES: To estimate the heritability of substance dependence and associated symptoms in a sample of Southwest California (Mission) Indians. METHODS: Families from eight contiguous Indian reservations were recruited in order to ascertain information on substance dependence symptoms and diagnoses using a semi-structured diagnostic interview. Dependence diagnoses for alcohol, marijuana, stimulants and a measure of regular tobacco usage, any drug dependence or tobacco usage were obtained. Composite measures of alcohol dependence symptoms for withdrawal, drinking severity, antisocial problems and interpersonal problems were constructed from the nine groups of symptoms summarized in the diagnostic interview. Heritability estimates were calculated using variance component methods, as implemented in SOLAR. RESULTS: In this population, marijuana dependence (0.38) and regular tobacco use (0.43), alcohol dependence (DSM-III-R 0.19; ICD-10, 0.29) and stimulant dependence (0.25) showed evidence for moderate genetic influences as determined by heritability estimates. Four phenotypes constructed using the composite symptoms of alcohol dependence revealed that withdrawal had the highest heritability estimate (0.71), followed by antisocial problems (0.36) and drinking severity (0.34). Symptom clusters reflecting interpersonal problems did not appear to be highly heritable (0.19). CONCLUSION: Marijuana dependence, regular tobacco usage and composite phenotypes constructed from alcohol dependence symptoms for antisocial problems, drinking severity and withdrawal generally have patterns of familial aggregation, suggesting that they can be successfully used for linkage analysis in this Southwest California Indian sample.     

Family-genetic study of executive functioning in attention-deficit/hyperactivity disorder: Evidence for an endophenotype?

This study examined familiality of attentional control and mental flexibility in multiplex attention-deficit/hyperactivity disorder (ADHD) families. The authors hypothesized that siblings of ADHD probands, although not behaviorally expressing ADHD, have deficits in these executive functions and that the performance of probands, unaffected siblings, and control participants are on a continuum. Participants (aged 6 to 17) were 25 ADHD probands with a family history of ADHD, their 25 unaffected siblings, and 48 control participants. The unaffected siblings did not differ from the ADHD probands on attentional control or on some measures of mental flexibility. Linear changes in performance across the groups reflected an intermediate position of the unaffected siblings between the probands and control participants. These results suggest that these executive functions may be suitable endophenotypes of ADHD.     

Executive functioning in children with attention-deficit/hyperactivity disorder: combined type with and without a stimulant medication history

Behavioral and neuropsychological functioning in unmedicated children with attention-deficit/hyperactivity disorder (ADHD) who have a history of medication treatment (Rx) versus those who are treatment na?ve (TN) has, to our knowledge, not been previously studied. Ninety-four children in four groups (ADHD/Rx, ADHD/TN, learning disabilities [LD], and controls) were evaluated, while unmedicated, on measures of achievement, neuropsychological functioning, and behavior. The ADHD/Rx group performed significantly better than the TN group on writing, Stroop interference, and measures of attention, and performed as well as the control group on executive functioning, verbal working memory, and academics. Behaviorally, the ADHD groups showed more difficulty with mood and externalizing behaviors compared with the LD and control groups, with the ADHD/TN performing the most poorly. Findings suggest that the ADHD/Rx group shows better executive and academic functioning even when unmedicated.