Publications by authors named "Susan Smalley"

65 Publications

Characterizing Emotional State Transitions During Prolonged Use of a Mindfulness and Meditation App: Observational Study.

JMIR Ment Health 2021 Mar 2;8(3):e19832. Epub 2021 Mar 2.

Bioinformatics and Systems Biology, University California San Diego, San Diego, CA, United States.

Background: The increasing demand for mental health care, a lack of mental health care providers, and unequal access to mental health care services have created a need for innovative approaches to mental health care. Digital device apps, including digital therapeutics, that provide recommendations and feedback for dealing with stress, depression, and other mental health issues can be used to adjust mood and ultimately show promise to help meet this demand. In addition, the recommendations delivered through such apps can also be tailored to an individual's needs (ie, personalized) and thereby potentially provide greater benefits than traditional "one-size-fits-all" recommendations.

Objective: This study aims to characterize individual transitions from one emotional state to another during the prolonged use of a digital app designed to provide a user with guided meditations based on their initial, potentially negative, emotional state. Understanding the factors that mediate such transitions can lead to improved recommendations for specific mindfulness and meditation interventions or activities (MMAs) provided in mental health apps.

Methods: We analyzed data collected during the use of the Stop, Breathe & Think (SBT) mindfulness app. The SBT app prompts users to input their emotional state before and immediately after engaging with MMAs recommended by the app. Data were collected from more than 650,000 SBT users engaging in nearly 5 million MMAs. We limited the scope of our analysis to users with 10 or more MMA sessions that included at least 6 basal emotional state evaluations. Using clustering techniques, we grouped emotions recorded by individual users and then applied longitudinal mixed effect models to assess the associations between individual recommended MMAs and transitions from one group of emotions to another.

Results: We found that basal emotional states have a strong influence on transitions from one emotional state to another after MMA engagement. We also found that different MMAs impact these transitions, and many were effective in eliciting a healthy transition but only under certain conditions. In addition, we observed gender and age effects on these transitions.

Conclusions: We found that the initial emotional state of an SBT app user determines the type of SBT MMAs that will have a favorable effect on their transition from one emotional state to another. Our results have implications for the design and use of guided mental health recommendations for digital device apps.
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http://dx.doi.org/10.2196/19832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967231PMC
March 2021

Association Between Improvement in Baseline Mood and Long-Term Use of a Mindfulness and Meditation App: Observational Study.

JMIR Ment Health 2019 May 8;6(5):e12617. Epub 2019 May 8.

Department of Biomedial Informatics, University of California San Diego, San Diego, CA, United States.

Background: The use of smartphone apps to monitor and deliver health care guidance and interventions has received considerable attention recently, particularly with regard to behavioral disorders, stress relief, negative emotional state, and poor mood in general. Unfortunately, there is little research investigating the long-term and repeated effects of apps meant to impact mood and emotional state.

Objective: We aimed to investigate the effects of both immediate point-of-intervention and long-term use (ie, at least 10 engagements) of a guided meditation and mindfulness smartphone app on users' emotional states. Data were collected from users of a mobile phone app developed by the company Stop, Breathe & Think (SBT) for achieving emotional wellness. To explore the long-term effects, we assessed changes in the users' basal emotional state before they completed an activity (eg, a guided meditation). We also assessed the immediate effects of the app on users' emotional states from preactivity to postactivity.

Methods: The SBT app collects information on the emotional state of the user before and after engagement in one or several mediation and mindfulness activities. These activities are recommended and provided by the app based on user input. We considered data on over 120,000 users of the app who collectively engaged in over 5.5 million sessions with the app during an approximate 2-year period. We focused our analysis on users who had at least 10 engagements with the app over an average of 6 months. We explored the changes in the emotional well-being of individuals with different emotional states at the time of their initial engagement with the app using mixed-effects models. In the process, we compared 2 different methods of classifying emotional states: (1) an expert-defined a priori mood classification and (2) an empirically driven cluster-based classification.

Results: We found that among long-term users of the app, there was an association between the length of use and a positive change in basal emotional state (4% positive mood increase on a 2-point scale every 10 sessions). We also found that individuals who were anxious or depressed tended to have a favorable long-term emotional transition (eg, from a sad emotional state to a happier emotional state) after using the app for an extended period (the odds ratio for achieving a positive emotional state was 3.2 and 6.2 for anxious and depressed individuals, respectively, compared with users with fewer sessions).

Conclusions: Our analyses provide evidence for an association between both immediate and long-term use of an app providing guided meditations and improvements in the emotional state.
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http://dx.doi.org/10.2196/12617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707590PMC
May 2019

Parsing heterogeneity in attention-deficit hyperactivity disorder using EEG-based subgroups.

J Child Psychol Psychiatry 2018 03 18;59(3):223-231. Epub 2017 Sep 18.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous condition for which multiple efforts to characterize brain state differences are underway. The objective of this study was to identify distinct subgroups of resting electroencephalography (EEG) profiles among children with and without ADHD and subsequently provide extensive clinical characterization of the subgroups.

Methods: Latent class analysis was used with resting state EEG recorded from a large sample of 781 children with and without ADHD (N = 620 ADHD, N = 161 Control), aged 6-18 years old. Behavioral and cognitive characteristics of the latent classes were derived from semistructured diagnostic interviews, parent completed behavior rating scales, and cognitive test performance.

Results: A five-class solution was the best fit for the data, of which four classes had a defining spectral power elevation. The distribution of ADHD and control subjects was similar across classes suggesting there is no one resting state EEG profile for children with or without ADHD. Specific latent classes demonstrated distinct behavioral and cognitive profiles. Those with elevated slow-wave activity (i.e. delta and theta band) had higher levels of externalizing behaviors and cognitive deficits. Latent subgroups with elevated alpha and beta power had higher levels of internalizing behaviors, emotion dysregulation, and intact cognitive functioning.

Conclusions: There is population-level heterogeneity in resting state EEG subgroups, which are associated with distinct behavioral and cognitive profiles. EEG measures may be more useful biomarkers of ADHD outcome or treatment response rather than diagnosis.
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http://dx.doi.org/10.1111/jcpp.12814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812789PMC
March 2018

A parietal biomarker for ADHD liability: as predicted by the distributed effects perspective model of ADHD.

Front Psychiatry 2015 7;6:63. Epub 2015 May 7.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles Semel Institute for Neuroscience and Human Behavior , Los Angeles, CA , USA.

Background: We previously hypothesized that poor task-directed sensory information processing should be indexed by increased weighting of right hemisphere (RH) biased attention and visuo-perceptual brain functions during task operations and have demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies. However, in our recent distributed effects model of ADHD, we surmised that this phenotype is not ADHD specific, but rather more broadly reflective of any circumstance that disrupts the induction and maintenance of an emergent task-directed neural architecture. Under this view, increased weighting of RH-biased attention and visuo-perceptual brain functions is expected to generally index neurocognitive sets that are not optimized for task-directed thought and action, and when durable expressed, liability for ADHD.

Method: The current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD was associated with common ADHD characteristics and comorbidities [i.e., ADHD risk factors (RFs)].

Results: Barring one exception (non-right handedness), we found that it was. Rightward parietal asymmetry (RPA) was associated with carrying the DRD4-7R risk allele, being male, having mood disorder, and having anxiety disorder. However, differences in the specific expression of RPA were observed, which are discussed in relation to possible unique mechanisms underlying ADHD liability in different ADHD RFs.

Conclusion: Rightward parietal asymmetry appears to be a durable feature of ADHD liability, as predicted by the Distributed Effects Perspective Model of ADHD. Moreover, variability in the expression of this phenotype may shed light on different sources of ADHD liability.
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http://dx.doi.org/10.3389/fpsyt.2015.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423436PMC
May 2015

Novel splice-affecting variants in CYP27A1 gene in two Chilean patients with Cerebrotendinous Xanthomatosis.

Genet Mol Biol 2015 Mar 17;38(1):30-6. Epub 2014 Mar 17.

Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile .

Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1.
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http://dx.doi.org/10.1590/S1415-475738120140087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415556PMC
March 2015

[Cerebrotendinous xanthomatosis: physiopathology, clinical manifestations and genetics].

Rev Med Chil 2014 May;142(5):616-22

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.
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http://dx.doi.org/10.4067/S0034-98872014000500010DOI Listing
May 2014

Community-Based Mindfulness Program for Disease Prevention and Health Promotion: Targeting Stress Reduction.

Am J Health Promot 2015 Sep-Oct;30(1):36-41. Epub 2014 Aug 27.

Purpose: Poorly managed stress leads to detrimental physical and psychological consequences that have implications for individual and community health. Evidence indicates that U.S. adults predominantly use unhealthy strategies for stress management. This study examines the impact of a community-based mindfulness training program on stress reduction.

Design: This study used a one-group pretest-posttest design.

Setting: The study took place at the UCLA Mindful Awareness Research Center in urban Los Angeles.

Subjects: A sample of N = 127 community residents (84% Caucasian, 74% female) were included in the study.

Intervention: Participants received mindfulness training through the Mindful Awareness Practices (MAPs) for Daily Living I.

Measures: Mindfulness, self-compassion, and perceived stress were measured at baseline and postintervention.

Analysis: Paired-sample t-tests were used to test for changes in outcome measures from baseline to postintervention. Hierarchical regression analysis was fit to examine whether change in self-reported mindfulness and self-compassion predicted postintervention perceived stress scores.

Results: There were statistically significant improvements in self-reported mindfulness (t = -10.67, p < .001, d = .90), self-compassion (t = -8.50, p < .001, d = .62), and perceived stress (t = 9.28, p < .001, d = -.78) at postintervention. Change in self-compassion predicted postintervention perceived stress (β = -.44, t = -5.06, p < .001), but change in mindfulness did not predict postintervention perceived stress (β = -.04, t = -.41, p = .68).

Conclusion: These results indicate that a community-based mindfulness training program can lead to reduced levels of psychological stress. Mindfulness training programs such as MAPs may offer a promising approach for general public health promotion through improving stress management in the urban community.
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http://dx.doi.org/10.4278/ajhp.131107-QUAN-567DOI Listing
January 2017

[Association between genetic polymorphisms of interleukin 6 (IL6), IL6R and IL18 with metabolic syndrome in obese Chilean children].

Rev Med Chil 2014 Mar;142(3):290-8

Background: Metabolic Syndrome (MS) is highly prevalent among obese children and adolescents and is considered a predictor for the development of type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an increase in circulating levels of interleukins 6 (IL6) and 18 (IL18), which in turn would depend on polymorphisms of IL6, IL6R and IL18 genes.

Aim: To evaluate the association between genetic polymorphisms of IL6 (rs1800795, rs1800796 and rs1800797), IL6R (rs2228145) and IL18 (rs360719, rs187238 and rs204355) and MS and/or its components in a sample of Chilean obese children.

Patients And Methods: These polymorphisms were genotyped in 259 obese children aged 10 ± 2 years with a body mass index of 26.1 ± 4.1 kg/m². Sixty eight had metabolic syndrome (26.3%). The association of their alleles, genotypes and haplotypes with the MS and its components was assessed.

Results: IL6, IL6R and IL18 variants showed no association with SM nor with any of the phenotypes that compose it. However, IL18 haplotypes (rs360719-rs187238-rs204355) TCT and CGT were associated with triglycerides ≤ 110 mg/dL and HDL < 40 mg/dL, respectively.

Conclusions: IL6 and IL6R variants are not associated with MS or with any of its phenotypes. Although an association between IL18 haplotypes and certain MS component has been detected herein, it is necessary to replicate our findings in independent studies due to the low frequency of these allele combinations detected in our sample.
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http://dx.doi.org/10.4067/S0034-98872014000300002DOI Listing
March 2014

Divergent metabolic phenotype between two sisters with congenital generalized lipodystrophy due to double AGPAT2 homozygous mutations. a clinical, genetic and in silico study.

PLoS One 2014 31;9(1):e87173. Epub 2014 Jan 31.

Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909042PMC
October 2014

Association of RNASEL and 8q24 variants with the presence and aggressiveness of hereditary and sporadic prostate cancer in a Hispanic population.

J Cell Mol Med 2014 Jan 14;18(1):125-33. Epub 2013 Nov 14.

Departamento de Urología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

To study the association between the polymorphisms Arg462Gln and Asp541Glu from the RNASEL gene (1q25), and the polymorphisms rs620861, rs1447295, rs6983267, rs7837328 from the chromosome 8q24 with the risk of presenting prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population. The study was performed on 21 control patients and 83 patients diagnosed with PCa. Polymorphisms were analysed from blood samples through real-time PCR by using TaqMan probes, and the genetic analysis was performed with the SNPStats program. Also, a comparison was performed between clinical characteristics of PCa and the presence of the different polymorphism genotypes by using the Minitab software. There was a significant association between the genotype G/G from the polymorphism rs6983267 with an overall increased risk of PCa, in patients both with or without family history of PCa (OR = 4.47, 95% CI = 1.05-18.94, P = 0.034 and OR = 3.57, 95% CI = 0.96-13.35, P = 0.037, respectively). Regarding clinical parameters, patients carrying the genotype C/C from the polymorphism Asp541Glu had significantly higher prostate-specific antigen (PSA) levels than patients carrying the other genotypes (P = 0.034). Moreover, patients with the genotype G/G of rs6983267 had higher PSA levels (P = 0.024). The polymorphism rs6983267 from region 3 of the chromosome 8q24 appears to be a prominent risk factor for PCa and a biomarker for cancer aggressiveness in the group of patients who presented higher levels of PSA at the time of diagnosis.
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http://dx.doi.org/10.1111/jcmm.12171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916124PMC
January 2014

Randomised controlled pilot trial of mindfulness training for stress reduction during pregnancy.

Psychol Health 2014 1;29(3):334-49. Epub 2013 Nov 1.

a Department of Psychology , University of California , Los Angeles , CA , USA.

This randomised controlled pilot trial tested a six-week mindfulness-based intervention in a sample of pregnant women experiencing high levels of perceived stress and pregnancy anxiety. Forty-seven women enrolled between 10 and 25 weeks gestation were randomly assigned to either a series of weekly Mindful Awareness Practices classes (n = 24) with home practice or to a reading control condition (n = 23). Hierarchical linear models of between-group differences in change over time demonstrated that participants in the mindfulness intervention experienced larger decreases from pre-to post-intervention in pregnancy-specific anxiety and pregnancy-related anxiety (PRA) than participants in the reading control condition. However, these effects were not sustained through follow-up at six weeks post-intervention. Participants in both groups experienced increased mindfulness, as well as decreased perceived stress and state anxiety over the course of the intervention and follow-up periods. This study is one of the first randomised controlled pilot trials of a mindfulness meditation intervention during pregnancy and provides some evidence that mindfulness training during pregnancy may effectively reduce PRA and worry. We discuss some of the dilemmas in pursuing this translational strategy and offer suggestions for researchers interested in conducting mind-body interventions during pregnancy.
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http://dx.doi.org/10.1080/08870446.2013.852670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160533PMC
March 2014

Melanocortin-4 receptor polymorphism rs17782313: association with obesity and eating in the absence of hunger in Chilean children.

Nutrition 2014 Feb 15;30(2):145-9. Epub 2013 Oct 15.

Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address:

Objective: The aim of this study was to assess the association between melanocortin-4 receptor (MC4R) rs17782313 alleles with obesity and eating behavior scores in Chilean children.

Methods: A case-control study was conducted with 139 normal-weight and 238 obese children (ages 6-12 y). MC4R rs17782313 genotypes were determined by quantitative-polymerase chain reaction allelic-discrimination assays. Eating behavior scores were evaluated in a subset of participants using the Chilean version of the Child Eating Behavior Questionnaire (CEBQ). Additionally, five normal-weight C-allele carriers of rs17782313 were matched by sex, age, and body mass index (BMI) to five TT homozygous children to carry out the Eating in the Absence of Hunger (EAH) test.

Results: The frequency of the C-allele of MC4R rs17782313 was higher in the obese group than in the control group, without achieving statistical significance (odds ratio, 1.4; 95% confidence interval, 0.8-2.4; P = 0.16). CEBQ scores of "enjoyment of food" were higher (P = 0.04) and "satiety responsiveness" were lower (P = 0.02) in children with CC genotype than in those with TT genotype matched by sex, age, and BMI. In the EAH test, all five non-obese carriers of the C-allele (three CC and two CT) showed increased sweet snack consumption compared with five matched (by sex-age-BMI) non-carriers after a preload meal, without achieving statistical significance (P = 0.06).

Conclusion: MC4R polymorphism rs17782313 may contribute to childhood obesity, affecting enjoyment of food, satiety responsiveness, and possibly eating in the absence of hunger.
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http://dx.doi.org/10.1016/j.nut.2013.05.030DOI Listing
February 2014

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

Authors:
S Hong Lee Stephan Ripke Benjamin M Neale Stephen V Faraone Shaun M Purcell Roy H Perlis Bryan J Mowry Anita Thapar Michael E Goddard John S Witte Devin Absher Ingrid Agartz Huda Akil Farooq Amin Ole A Andreassen Adebayo Anjorin Richard Anney Verneri Anttila Dan E Arking Philip Asherson Maria H Azevedo Lena Backlund Judith A Badner Anthony J Bailey Tobias Banaschewski Jack D Barchas Michael R Barnes Thomas B Barrett Nicholas Bass Agatino Battaglia Michael Bauer Mònica Bayés Frank Bellivier Sarah E Bergen Wade Berrettini Catalina Betancur Thomas Bettecken Joseph Biederman Elisabeth B Binder Donald W Black Douglas H R Blackwood Cinnamon S Bloss Michael Boehnke Dorret I Boomsma Gerome Breen René Breuer Richard Bruggeman Paul Cormican Nancy G Buccola Jan K Buitelaar William E Bunney Joseph D Buxbaum William F Byerley Enda M Byrne Sian Caesar Wiepke Cahn Rita M Cantor Miguel Casas Aravinda Chakravarti Kimberly Chambert Khalid Choudhury Sven Cichon C Robert Cloninger David A Collier Edwin H Cook Hilary Coon Bru Cormand Aiden Corvin William H Coryell David W Craig Ian W Craig Jennifer Crosbie Michael L Cuccaro David Curtis Darina Czamara Susmita Datta Geraldine Dawson Richard Day Eco J De Geus Franziska Degenhardt Srdjan Djurovic Gary J Donohoe Alysa E Doyle Jubao Duan Frank Dudbridge Eftichia Duketis Richard P Ebstein Howard J Edenberg Josephine Elia Sean Ennis Bruno Etain Ayman Fanous Anne E Farmer I Nicol Ferrier Matthew Flickinger Eric Fombonne Tatiana Foroud Josef Frank Barbara Franke Christine Fraser Robert Freedman Nelson B Freimer Christine M Freitag Marion Friedl Louise Frisén Louise Gallagher Pablo V Gejman Lyudmila Georgieva Elliot S Gershon Daniel H Geschwind Ina Giegling Michael Gill Scott D Gordon Katherine Gordon-Smith Elaine K Green Tiffany A Greenwood Dorothy E Grice Magdalena Gross Detelina Grozeva Weihua Guan Hugh Gurling Lieuwe De Haan Jonathan L Haines Hakon Hakonarson Joachim Hallmayer Steven P Hamilton Marian L Hamshere Thomas F Hansen Annette M Hartmann Martin Hautzinger Andrew C Heath Anjali K Henders Stefan Herms Ian B Hickie Maria Hipolito Susanne Hoefels Peter A Holmans Florian Holsboer Witte J Hoogendijk Jouke-Jan Hottenga Christina M Hultman Vanessa Hus Andrés Ingason Marcus Ising Stéphane Jamain Edward G Jones Ian Jones Lisa Jones Jung-Ying Tzeng Anna K Kähler René S Kahn Radhika Kandaswamy Matthew C Keller James L Kennedy Elaine Kenny Lindsey Kent Yunjung Kim George K Kirov Sabine M Klauck Lambertus Klei James A Knowles Martin A Kohli Daniel L Koller Bettina Konte Ania Korszun Lydia Krabbendam Robert Krasucki Jonna Kuntsi Phoenix Kwan Mikael Landén Niklas Långström Mark Lathrop Jacob Lawrence William B Lawson Marion Leboyer David H Ledbetter Phil H Lee Todd Lencz Klaus-Peter Lesch Douglas F Levinson Cathryn M Lewis Jun Li Paul Lichtenstein Jeffrey A Lieberman Dan-Yu Lin Don H Linszen Chunyu Liu Falk W Lohoff Sandra K Loo Catherine Lord Jennifer K Lowe Susanne Lucae Donald J MacIntyre Pamela A F Madden Elena Maestrini Patrik K E Magnusson Pamela B Mahon Wolfgang Maier Anil K Malhotra Shrikant M Mane Christa L Martin Nicholas G Martin Manuel Mattheisen Keith Matthews Morten Mattingsdal Steven A McCarroll Kevin A McGhee James J McGough Patrick J McGrath Peter McGuffin Melvin G McInnis Andrew McIntosh Rebecca McKinney Alan W McLean Francis J McMahon William M McMahon Andrew McQuillin Helena Medeiros Sarah E Medland Sandra Meier Ingrid Melle Fan Meng Jobst Meyer Christel M Middeldorp Lefkos Middleton Vihra Milanova Ana Miranda Anthony P Monaco Grant W Montgomery Jennifer L Moran Daniel Moreno-De-Luca Gunnar Morken Derek W Morris Eric M Morrow Valentina Moskvina Pierandrea Muglia Thomas W Mühleisen Walter J Muir Bertram Müller-Myhsok Michael Murtha Richard M Myers Inez Myin-Germeys Michael C Neale Stan F Nelson Caroline M Nievergelt Ivan Nikolov Vishwajit Nimgaonkar Willem A Nolen Markus M Nöthen John I Nurnberger Evaristus A Nwulia Dale R Nyholt Colm O'Dushlaine Robert D Oades Ann Olincy Guiomar Oliveira Line Olsen Roel A Ophoff Urban Osby Michael J Owen Aarno Palotie Jeremy R Parr Andrew D Paterson Carlos N Pato Michele T Pato Brenda W Penninx Michele L Pergadia Margaret A Pericak-Vance Benjamin S Pickard Jonathan Pimm Joseph Piven Danielle Posthuma James B Potash Fritz Poustka Peter Propping Vinay Puri Digby J Quested Emma M Quinn Josep Antoni Ramos-Quiroga Henrik B Rasmussen Soumya Raychaudhuri Karola Rehnström Andreas Reif Marta Ribasés John P Rice Marcella Rietschel Kathryn Roeder Herbert Roeyers Lizzy Rossin Aribert Rothenberger Guy Rouleau Douglas Ruderfer Dan Rujescu Alan R Sanders Stephan J Sanders Susan L Santangelo Joseph A Sergeant Russell Schachar Martin Schalling Alan F Schatzberg William A Scheftner Gerard D Schellenberg Stephen W Scherer Nicholas J Schork Thomas G Schulze Johannes Schumacher Markus Schwarz Edward Scolnick Laura J Scott Jianxin Shi Paul D Shilling Stanley I Shyn Jeremy M Silverman Susan L Slager Susan L Smalley Johannes H Smit Erin N Smith Edmund J S Sonuga-Barke David St Clair Matthew State Michael Steffens Hans-Christoph Steinhausen John S Strauss Jana Strohmaier T Scott Stroup James S Sutcliffe Peter Szatmari Szabocls Szelinger Srinivasa Thirumalai Robert C Thompson Alexandre A Todorov Federica Tozzi Jens Treutlein Manfred Uhr Edwin J C G van den Oord Gerard Van Grootheest Jim Van Os Astrid M Vicente Veronica J Vieland John B Vincent Peter M Visscher Christopher A Walsh Thomas H Wassink Stanley J Watson Myrna M Weissman Thomas Werge Thomas F Wienker Ellen M Wijsman Gonneke Willemsen Nigel Williams A Jeremy Willsey Stephanie H Witt Wei Xu Allan H Young Timothy W Yu Stanley Zammit Peter P Zandi Peng Zhang Frans G Zitman Sebastian Zöllner Bernie Devlin John R Kelsoe Pamela Sklar Mark J Daly Michael C O'Donovan Nicholas Craddock Patrick F Sullivan Jordan W Smoller Kenneth S Kendler Naomi R Wray

Nat Genet 2013 Sep 11;45(9):984-94. Epub 2013 Aug 11.

The University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia.

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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http://dx.doi.org/10.1038/ng.2711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800159PMC
September 2013

Characterization of the theta to beta ratio in ADHD: identifying potential sources of heterogeneity.

J Atten Disord 2013 Jul 20;17(5):384-92. Epub 2012 Dec 20.

University of California Los Angeles, USA.

Objective: The goal of this study is to characterize the theta to beta ratio (THBR) obtained from electroencephalogram (EEG) measures, in a large sample of community and clinical participants with regard to (a) ADHD diagnosis and subtypes, (b) common psychiatric comorbidities, and (c) cognitive correlates.

Method: The sample includes 871 participants (595 youth and 276 adults) with and without ADHD. All participants underwent extensive assessment, including semistructured diagnostic interviews, cognitive testing, and EEG recording.

Results: The THBR did not differ significantly by ADHD status for youth but was significantly lower in adults with ADHD compared with controls. ADHD subtype and psychiatric comorbidities such as disruptive behavior disorders and depression have opposing and significant mediating effects on the THBR.

Conclusion: The THBR is affected by several mediating factors associated with ADHD such as ADHD subtype and psychiatric comorbidity. More research is needed to understand the functional significance of the THBR in ADHD.
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http://dx.doi.org/10.1177/1087054712468050DOI Listing
July 2013

APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.

BMC Med Genet 2012 Nov 15;13:106. Epub 2012 Nov 15.

Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Alameda, Santiago, Chile.

Background: Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family.

Methods: We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives.

Results: A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls.

Conclusion: The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.
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http://dx.doi.org/10.1186/1471-2350-13-106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523038PMC
November 2012

Sex-specific influence of DRD2 on ADHD-type temperament in a large population-based birth cohort.

Psychiatr Genet 2012 Aug;22(4):197-201

Public Health Genomics Unit, Institute for Molecular Medicine Finland FIMM, University of Helsinki and National Institute for Health and Welfare, Helsinki, Finland.

Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a significant public-health impact. Previously, we described a candidate gene study in a population-based birth cohort that demonstrated an association with ADHD-affected males and the dopamine receptor D2 (DRD2). The current study evaluates potential associations of dopamine receptor genes and Cloninger temperament traits within this same sample. Participants with stringent lifetime ADHD diagnoses were ascertained systematically from the genetically isolated Northern Finland 1986 Birth Cohort (n=9432), resulting in 178 cases and 157 controls. Markers in all known dopamine receptor genes were genotyped. We report an association of DRD2 with low Persistence in females (rs1079727 P=0.02, rs1124491 P=0.02, rs1800497 P=0.03). The associated DRD2 minor allelic haplotype (CAA, P=0.03) is the same haplotype we previously associated with ADHD in males in this birth cohort. The current study further supports previous results on the role of DRD2 in individuals with ADHD. Investigations suggest that DRD2 may have an impact on both males and females, but the particular outcome appears sex-specific, manifesting as ADHD in males and low Persistence in females. Furthermore, these findings suggest that the putative role of low Persistence as an endophenotype for ADHD deserves further investigation.
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http://dx.doi.org/10.1097/YPG.0b013e32834c0cc8DOI Listing
August 2012

Genome-wide association study of intelligence: additive effects of novel brain expressed genes.

J Am Acad Child Adolesc Psychiatry 2012 Apr 28;51(4):432-440.e2. Epub 2012 Feb 28.

University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA.

Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability.

Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally homogeneous family sample of 656 individuals with at least one child affected by attention-deficit/hyperactivity disorder (ADHD).

Results: Haplotype trend regression analysis with sliding four-SNP windows identified haplotypes of genome-wide significance in genes involved in synaptic signaling (KIF16B; p = 1.27E-08) and neurodevelopment (PAX5; p = 3.58E-08), and highlight findings from a recent genetic study of cognitive ability (RXRA; p = 7.7E-08; GYPC; p = 2.5E-07). Further interrogation of SNPs within top haplotypes reveals that the minor alleles are associated with higher intelligence, whereas others are associated with relatively lower (but still average range) intelligence. Effects of the eight genes are additive, as a greater number of the associated genotypes in a given individual predict higher intelligence (p = 5.36E-08) and account for 8% of variance in intelligence.

Conclusions: Analyses that examine additive genetic effects may be useful in identifying regions where the additive effects of SNPs have a significant effect on phenotype. These results describe novel variants and additive effects of genes involved in brain development on variability in intelligence within an ADHD sample. The precise mechanisms of these loci in relation to determining individual differences in general cognitive ability require further investigation.
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http://dx.doi.org/10.1016/j.jaac.2012.01.006DOI Listing
April 2012

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

Am J Psychiatry 2012 Feb;169(2):195-204

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, and School of Medicine, Cardiff University, Cardiff, UK.

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology.

Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium.

Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder.

Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601405PMC
http://dx.doi.org/10.1176/appi.ajp.2011.11060822DOI Listing
February 2012

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

Nat Genet 2011 Dec 4;44(1):78-84. Epub 2011 Dec 4.

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.
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http://dx.doi.org/10.1038/ng.1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4310555PMC
December 2011

Brain growth rate abnormalities visualized in adolescents with autism.

Hum Brain Mapp 2013 Feb 20;34(2):425-36. Epub 2011 Oct 20.

Laboratory of Neuro Imaging, University of California Los Angeles School of Medicine, Los Angeles, California, USA.

Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects.
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http://dx.doi.org/10.1002/hbm.21441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144412PMC
February 2013

Association between eating behavior scores and obesity in Chilean children.

Nutr J 2011 Oct 11;10:108. Epub 2011 Oct 11.

Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.

Background: Inadequate eating behavior and physical inactivity contribute to the current epidemic of childhood obesity. The aim of this study was to assess the association between eating behavior scores and childhood obesity in Chilean children.

Design And Methods: We recruited 126 obese, 44 overweight and 124 normal-weight Chilean children (6-12 years-old; both genders) according to the International Obesity Task Force (IOTF) criteria. Eating behavior scores were calculated using the Child Eating Behavior Questionnaire (CEBQ). Factorial analysis in the culturally-adapted questionnaire for Chilean population was used to confirm the original eight-factor structure of CEBQ. The Cronbach's alpha statistic (>0.7 in most subscales) was used to assess internal consistency. Non-parametric methods were used to assess case-control associations.

Results: Eating behavior scores were strongly associated with childhood obesity in Chilean children. Childhood obesity was directly associated with high scores in the subscales "enjoyment of food" (P < 0.0001), "emotional overeating" (P < 0.001) and "food responsiveness" (P < 0.0001). Food-avoidant subscales "satiety responsiveness" and "slowness in eating" were inversely associated with childhood obesity (P < 0.001). There was a graded relation between the magnitude of these eating behavior scores across groups of normal-weight, overweight and obesity groups.

Conclusion: Our study shows a strong and graded association between specific eating behavior scores and childhood obesity in Chile.
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http://dx.doi.org/10.1186/1475-2891-10-108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213088PMC
October 2011

Genome-wide association study of the child behavior checklist dysregulation profile.

J Am Acad Child Adolesc Psychiatry 2011 Aug 13;50(8):807-17.e8. Epub 2011 Jul 13.

University of Massachusetts Medical School, Worcester, MA 01655, USA.

Objective: A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD).

Method: Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK.

Results: CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA (N = 128) and the MGH (N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p < 5E-05: TMEM132D, LRRC7, SEMA3A, ALK, and STIP1.

Conclusions: We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP.
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http://dx.doi.org/10.1016/j.jaac.2011.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143361PMC
August 2011

Family-based genome-wide association scan of attention-deficit/hyperactivity disorder.

J Am Acad Child Adolesc Psychiatry 2010 Sep 14;49(9):898-905.e3. Epub 2010 May 14.

Massachusetts General Hospital, 55 Fruit Street-Warren 705, Boston, MA 02114, USA.

Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD.

Method: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families.

Results: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9.

Conclusions: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.
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http://dx.doi.org/10.1016/j.jaac.2010.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730251PMC
September 2010

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder.

J Am Acad Child Adolesc Psychiatry 2010 Sep 1;49(9):884-97. Epub 2010 Aug 1.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.

Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power.

Method: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis.

Results: No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder.

Conclusions: Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.
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http://dx.doi.org/10.1016/j.jaac.2010.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928252PMC
September 2010

Atypical EEG beta asymmetry in adults with ADHD.

Neuropsychologia 2010 Oct 10;48(12):3532-9. Epub 2010 Aug 10.

Department of Psychiatry and Biobehavioral Sciences, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA 90024, USA.

Background: Abnormal brain laterality (ABL) is well established in ADHD. However, its clinical specificity and association to cognitive and clinical symptoms is not yet understood. Previous studies indicate increased right hemisphere (RH) contribution in both ADHD and reading impaired samples. The current study investigates whether this ABL characteristic occurs in adults with ADHD absent comorbid language impairment.

Methods: EEG beta asymmetry was compared in 35 adult ADHD subjects and 104 controls during rest and active cognition. Group differences in beta asymmetry were then further evaluated for association to linguistic and attentional abilities, as well as association to beta asymmetry measures across different brain regions.

Results: Adults with ADHD showed pronounced rightward beta asymmetry (p=.00001) in inferior parietal regions (P8-P7) during a continuous performance task (CPT) that could not be attributed to linguistic ability. Among ADHD subjects only, greater rightward beta asymmetry at this measure was correlated with better CPT performance. Furthermore, this measure showed a lack of normal association (i.e., observed in controls) to left-biased processing in temporal-parietal (TP8-TP7) brain regions important for higher order language functions.

Conclusion: Adult ADHD involves abnormally increased right-biased contribution to CPT processing that could not be attributed to poor language ability. This appears to also involve abnormal recruitment of LH linguistic processing regions and represents an alternative, albeit less effective, CPT processing strategy. These findings suggest different pathophysiologic mechanisms likely underlie RH biased processing in ADHD and reading impaired samples.
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http://dx.doi.org/10.1016/j.neuropsychologia.2010.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965023PMC
October 2010

Familial clustering and DRD4 effects on electroencephalogram measures in multiplex families with attention deficit/hyperactivity disorder.

J Am Acad Child Adolesc Psychiatry 2010 Apr;49(4):368-77

Semel Institute for Neuroscience and Human Behavior and David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.

Objective: The current study tests electroencephalogram (EEG) measures as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD) by examining sibling and parent-offspring similarity, familial clustering with the disorder, and association with the dopamine receptor D4 (DRD4) candidate gene.

Method: The sample consists of 531 participants (191 parents and 340 children) from 132 multiplex families with ADHD who participated in a larger genetics study. All members of the families underwent extensive assessment including semi-structured diagnostic interviews and EEG recording.

Results: Strong sibling similarity and parent-offspring correlations in EEG power emerged, suggesting high trait heritability. Increased theta power was observed among children with ADHD when compared with unaffected children, and there were no differences according to ADHD subtype. Within the parent sample, ADHD diagnostic status and ADHD subtype group differences emerged in the theta, alpha, and beta frequency bands. DRD4 effects for both parents and children were apparent in the beta frequency band and for children only in the theta frequency band.

Conclusions: This study suggests that EEG measures are a promising avenue of study in the search for putative endophenotypes for ADHD, and that variability at the DRD4 gene may contribute to this endophenotype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919766PMC
April 2010

On genome-wide association studies for family-based designs: an integrative analysis approach combining ascertained family samples with unselected controls.

Am J Hum Genet 2010 Apr 25;86(4):573-80. Epub 2010 Mar 25.

Channing Laboratories, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Large numbers of control individuals with genome-wide genotype data are now available through various databases. These controls are regularly used in case-control genome-wide association studies (GWAS) to increase the statistical power. Controls are often "unselected" for the disease of interest and are not matched to cases in terms of confounding factors, making the studies more vulnerable to confounding as a result of population stratification. In this communication, we demonstrate that family-based designs can integrate unselected controls from other studies into the analysis without compromising the robustness of family-based designs against genetic confounding. The result is a hybrid case-control family-based analysis that achieves higher power levels than population-based studies with the same number of cases and controls. This strategy is widely applicable and works ideally for all situations in which both family and case-control data are available. The approach consists of three steps. First, we perform a standard family-based association test that does not utilize the between-family component. Second, we use the between-family information in conjunction with the genotypes from unselected controls in a Cochran-Armitage trend test. The p values from this step are then calculated by rank ordering the individual Cochran-Armitage trend test statistics for the genotype markers. Third, we generate a combined p value with the association p values from the first two steps. Simulation studies are used to assess the achievable power levels of this method compared to standard analysis approaches. We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls.
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http://dx.doi.org/10.1016/j.ajhg.2010.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850439PMC
April 2010

Independent contributions of cognitive functioning and social risk factors to symptoms of ADHD in two nordic populations-based cohorts.

Dev Neuropsychol 2009 ;34(6):721-35

Department of Psychology, Uppsala University, Uppsala, Sweden.

This study examined independent contributions of executive functioning (EF), state regulation (SR), and social risk factors to symptom dimensions of attention deficit hyperactivity disorder (ADHD) in two cohorts, which included 221 Norwegian children and 294 Finnish adolescents. Independent contributions of EF and SR were shown in the Norwegian cohort and EF contributed independently in the Finnish cohort. When controlling for each symptom dimension, cognitive functioning and social risk factors were differentially associated with inattention and hyperactivity/impulsivity symptoms. The results show the need to include both social risk factors and cognitive functioning to obtain a better understanding of ADHD symptoms.
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http://dx.doi.org/10.1080/87565640903265111DOI Listing
June 2010

ADHD familial loading and abnormal EEG alpha asymmetry in children with ADHD.

J Psychiatr Res 2010 Jul 16;44(9):605-15. Epub 2009 Dec 16.

Division of Child and Adolescent Psychiatry and Center for Neurobehavioral Genetics at the UCLA Semel Institute, 760 Westwood Plaza, Room 47-448, Los Angeles, CA 90095, United States.

Objective: Abnormal brain laterality (ABL) is indicated in ADHD. ADHD and brain laterality are heritable. Genetic factors contributing to lateralization of brain function may contribute to ADHD. If so, increased ADHD family loading should be associated with greater ABL. Previous studies have shown increased rightward alpha asymmetry in ADHD. We tested whether this was more pronounced in ADHD children with increased ADHD family loading.

Methods: We compared EEG alpha asymmetry at rest and during the Conner's Continuous Performance Test (CPT) in ADHD children with and without ADHD affected parents, and replicated our findings in a second larger sample. The replication study additionally stratified the parent-affected sample by parental persistent versus non-persistent ADHD status, increased spatial resolution of EEG measures, and assessed low versus high-alpha.

Results: Study-1: the parent-affected group showed increased rightward asymmetry across frontal and central regions and reduced rightward parietal asymmetry during an eyes closed (EC) condition, as well as increasing rightward parietal asymmetry with advancing age during the CPT. Study-2 replicated these findings and further delineated influences of low versus high-alpha, recording site, and effects of parental persistent versus non-persistent ADHD status.

Conclusion: Increased ADHD familial loading was associated with increased rightward frontal asymmetry. In contrast, increased rightward parietal asymmetry was associated with reduced ADHD family loading. Frontal results are consistent with an ADHD endophenotype. Parietal results suggest an ADHD adaptive trait prevalent with less ADHD family loading. Age effects indicate a unique developmental course among ADHD children whose parents have non-persistent ADHD.
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http://dx.doi.org/10.1016/j.jpsychires.2009.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878884PMC
July 2010

A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

J Am Acad Child Adolesc Psychiatry 2009 Dec;48(12):1155-64

Semel Institute for Neuroscience & Human Behavior and David Geffen School of Medicine, University of California, Los Angeles, USA.

Objective: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD).

Method: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes.

Results: Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p = .01), with a suggested trend for catechol-O-methyltransferase (COMT) (p = .04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p = .008), DRD4 exon 3 VNTR (p = .006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p = .02). Irritability was predicted by COMT (p = .02). Vegetative symptoms were predicted by 5HTTLPR (p = .003). No significant effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25).

Conclusions: This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects.
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http://dx.doi.org/10.1097/CHI.0b013e3181bc72e3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888980PMC
December 2009