Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples. Molecular Psychiatry (2006) 11, 934-953.

Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM-IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM-IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (l sib ) of 9.0. Estimated sibling correlations around 0.2-0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM-IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings. INTRODUCTIONAttention deficit hyperactivity disorder (ADHD) is a common and heritable disorder that starts in early childhood and is characterized by developmentally inappropriate levels of hyperactive, impulsive, and inattentive behaviors accompanied by psychosocial impairments. The disorder is known to aggregate in families, with recent estimates suggesting a fourto sixfold increase in the risk for ADHD among first-degree relatives of ADHD probands [Faraone et al., 2000;Brookes et al., 2006a]. Twin studies using parent and teacher rated ADHD symptom scales demonstrate the predominant role of genetic factors with heritability estimates in the range 60-90% [Thapar et al., 1999;Faraone et al., 2005]. Molecular genetic studies using candidate gene association approaches have yielded positive findings with dopamine and related monoamine neurotransmitter genes, in particular with genetic variants of the dopamine transporter, dopamine D4 and D5 receptor genes [reviewed in Asherson and The Image Consortium, 2004;Faraone et al., 2005;Brookes et al., 2006b;Li et al., 2006;Asherson et al., 2007]. Linkage studies using affected sib-pair or extended pedigree approaches have identified chromosomal regions containing putative risk alleles for ADHD [Fisher et al., 2002a;Bakker et al., 2003;Ogdie et al., 2003Ogdie et al., , 2004Ogdie et al., , 2006Arcos-Burgos et al., 2004;Hebebrand et al., 2006].I...

The influence of pregnancy on multiple sclerosis was studied in 338 women by determining in each trimester of pregnancy and post partum the number of relapses and the corresponding relapse rate. Eighty-five relapses occurred in association with 199 pregnancies, most (65) in the postpartum period, and a low number of relapses (2) were recorded in the last trimester of pregnancy. Comparing the average exacerbation rate of the study group with that of patients with multiple sclerosis in Israel (0.28 relapses per person per year), we found a statistically significant decrease in the third trimester (0.04) and a high increase in the first three months post partum (0.82). This pattern of remissions at the end of pregnancy and exacerbations post partum is similar to that observed in other putative autoimmune diseases.

The influence of pregnancy on multiple sclerosis was studied in 338 women by determining in each trimester of pregnancy and post partum the number of relapses and the corresponding relapse rate. Eighty-five relapses occurred in association with 1 9 pregnancies, most (65) in the postpartum period, and a low number of relapses ( 2 ) were recorded in the last trimester of pregnancy. Comparing the average exacerbation rate of the study group with that of patients with multiple sclerosis in Israel (0.28 relapses per person per year), we found a statistically significant decrease in the third trimester (0.04) and a high increase in the first three months postpartum (0.82). This pattern of remissions at the end of pregnancy and exacerbations post partum is similar to that observed in other putative autoimmune diseases. Our aim in the present study was not just to assess the general influence of pregnancy on MS, but to compare with other MS patients the number of relapses occurring in each trimester of pregnancy and post partum as well as the corresponding relapse rate. The study was undertaken because a number of putative autoimmune diseases show clinical remissions in the second half of pregnancy as well as exacerbations post partum {Sl. Materials and MethodsNationwide studies have been carried out in Israel since 1960 to identify and classify all cases of MS in that country. The National Neurological Disease Registry, maintained by the Uri Leibowitz Neuroepidemiology Unit of the Department of Neurology at Hadassah University Hospital in Jerusalem, was the source of patient records 1131.Criteria for the diagnosis of MS were those used by the Neuroepidemiology Unit, and are a modification of those published by McDonald and Halliday [15}, Bauer [2], and Rose and colleagues { 2 11. Patients were grouped in one of three diagnostic categories: clinically definite, probable, or possible MS. Our study included all clinically definite and probable cases since 1960. In each case we indicated the number and dates of pregnancies, year of onset of the disease, and number and dates of relapses occurring during pregnancy or post partum. A relapse was defined as the appearance of new symptoms in addition to confirmation of new signs or objective evidence of aggravation upon medical neurological examination. The first exacerbation was counted as the onset of the disease. We looked for the relapses occurring during pregnancy and related each relapse to the month of pregnancy during which it occurred. Nine months of pregnancy (divided into three terms) and 6 months of the postpartum course were reviewed. Patients in whom relapses occurred during pregnancy or post partum were followed for an additional 1.5 years after the end of the postpartum period. In those patients we counted the number of relapses occurring from the 15th to the 33rd month, considering the beginning of the pregnancy as the first month.In each period we calculated the relapse rate (number of relapses per person per year) using a x2 test. The denominator was the total ...