Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood characterized by inattention, excessive motor activity, impulsivity, and distractibility. It is associated with serious disability in children, adolescents and adults. 1 The etiology of the disorder is unknown, but it has a strong genetic component. Pharmacological and biochemical studies have suggested that dopaminergic and noradrenergic systems are involved. 2 Using a sample of affected children and their parents we have found preferential transmission of alleles at polymorphisms at the dopamine transporter (DAT1), RR = 1.2 (1.05-1.37), P = 0.006, re-confirming and extending our previous findings for DAT1 3 (new sample one-tailed P = 0.039); dopamine-␤-hydroxylase (DBH), RR = 1.31 (1.09-1.56), P = 0.0027; and the dopamine D5 receptor (DRD5), RR = 1.67 (1.29-2.15), P = 0.00005. Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR DAT1 = 1.29 (1.04-1.59), RR DBH = 1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR = 1.59 (1.05-2.42). TDT analysis of complete trios supports the HHRR analysis, with P Ͻ 0.05, for DAT1 P Ͻ 0.005 and DBH and P Ͻ 0.01 for DRD5. Attributable fractions for DAT1, DBH and DRD5 are calculated at 0.08, 0.12 and 0.20 respectively.ADHD affects between 4% and 6% of the school-age population. 4,5 It affects boys two to three times more frequently than girls and leads to significant behavioral problems, impaired family and social relationships and major difficulties in school. Many children with ADHD develop conduct disorder and the long-term outcome is poor. 1 ADHD is familial 6 and twin studies estimate heritability (h 2 ) at 80-90%. [7][8][9] The mode of transmission is unknown, but is likely to be due to many genes, each of small effect. Overall 1st.Deg.Rel is 5-6, 10 suggesting that relative risks at individual loci will be small, and below the resolution of linkage studies. 11 We 3 previously confirmed an association 12 with the 480-bp allele of a VNTR situated in the 3Ј untranslated region of the DAT1 gene. 13 A further replication of this finding is provided by Waldman et al. 14 However, recent work proposes a more complicated neurochemical process including relative hypo-and hyper-dopaminergic function and involving the noradrenergic system. 2 We therefore extended our studies to include other monoamine-related genes.The dopamine transporter gene is a member of a family of Na + and Cl − dependent neurotransmitter transporters containing twelve transmembrane domains. 15 This gene confers all of the pharmacological properties of the rat dopamine re-uptake carrier 16 including the capacity to bind cocaine and other psychostimulant drugs. A 40-bp polymorphic tandem repeat was identified in the 3Ј UTR and was used in the present study. Dopamine-␤-hydroxylase (D␤H) catalyses the conversion of dopamine to noradrenaline. The gene (DBH) is closely linked to the ABO blood group on chromosome 9q34. Enzyme activity in serum or plasma is a stable, hi...

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Brain network hubs are both highly connected and highly inter-connected, forming a critical communication backbone for coherent neural dynamics. The mechanisms driving this organization are poorly understood. Using diffusion-weighted magnetic resonance imaging in twins, we identify a major role for genes, showing that they preferentially influence connectivity strength between network hubs of the human connectome. Using transcriptomic atlas data, we show that connected hubs demonstrate tight coupling of transcriptional activity related to metabolic and cytoarchitectonic similarity. Finally, comparing over thirteen generative models of network growth, we show that purely stochastic processes cannot explain the precise wiring patterns of hubs, and that model performance can be improved by incorporating genetic constraints. Our findings indicate that genes play a strong and preferential role in shaping the functionally valuable, metabolically costly connections between connectome hubs.