Significant terms involving paternal age at birth in linear and linear mixed-effects models for endophenotype performance.

<p>Abbreviations: CI, confidence interval; CPT-IP, Continuous Performance Test, Identical Pairs version.</p>a<p>Only terms involving paternal age at subject birth with an associated <i>P</i> value <0.05 are reported, and only endophenotypes with such terms are reported.</p>b<p>Slope and confidence intervals are in units of a 10-year increase in paternal age at birth. A <i>positive</i> slope indicates that subjects with older fathers perform <i>better</i> on the endophenotype.</p>c<p><i>P</i> values are based on linear models with effects for paternal age, paternal age–by-gender, and paternal age–by–multiplex status, with subject age, test site, subject gender, and parental education as covariates.</p>d<p>After adjusting for multiple comparisons accounting for the 16 endophenotypes, none of the results are significant at an overall Type I error level of 5%.</p>e<p><i>P</i> values are based on linear mixed-effects models with effects for paternal age, paternal age–by-gender, and paternal age–by–multiplex status, with group (proband versus sibling), subject age, test site, subject gender, parental education, and all second-order interactions involving group as covariates. Family membership served as a random effect to account for the relatedness of observations among family members.</p

Demographic and clinical characteristics of schizophrenia subjects and unaffected siblings.

<p>Abbreviations: CI, confidence interval; SANS, Schedule for the Assessment of Negative Symptoms; SAPS, Schedule for the Assessment of Positive Symptoms; SD, standard deviation; WRAT-3, Wide Range Achievement Test, 3rd edition.</p>a<p>Unaffected siblings represent 279 families, of which 17 (6%) were multiplex.</p>b<p>Between-group <i>P</i> values are based on generalized linear mixed-effects models for categorical variables and linear mixed-effects models for continuous variables; <i>P</i> values were not computed for race, multiplex status, parental education, or age at onset of symptoms.</p>c<p>For continuous variables, differences between groups (probands – unaffected siblings) and 95% CIs for differences are based on linear mixed-effects models; for categorical variables, odds ratios and 95% CIs for odds ratios are based on generalized linear mixed-effects models. CIs are shown only for variables where the <i>P</i> value for the between-group test is <0.05.</p>d<p>4 missing values for schizophrenia subjects; 2 missing values for unaffected siblings.</p>e<p>Multiplex families were those for which at least one parent or sibling of the proband had a history of schizophrenia or schizoaffective disorder.</p>f<p>2 missing values for schizophrenia subjects; 2 missing values for unaffected siblings.</p>g<p>6 missing values for schizophrenia subjects; 3 missing values for unaffected siblings.</p>h<p>10 missing values for schizophrenia subjects; 12 missing values for unaffected siblings.</p>i<p>5 missing values for schizophrenia subjects.</p>j<p>7 missing values for schizophrenia subjects; 73 missing values for unaffected siblings.</p>k<p>7 missing values for schizophrenia subjects; 74 missing values for unaffected siblings.</p

Unadjusted endophenotypes for schizophrenia subjects and unaffected siblings.

<p>Abbreviations: CNB, Computerized Neurocognitive Battery; CPT-IP, Continuous Performance Test, Identical Pairs version; CVLT, California Verbal Learning Test; DS-CPT, Degraded Stimulus Continuous Performance Test; LNS, Letter-Number Span; PPI, prepulse inhibition.</p>a<p>Proportion correct out of a maximum of 60 trials.</p>b<p>Prepulse inhibition using 60 msec pulses.</p><p>100 × [1 − (magnitude of startle to pulse preceded by prepulse/magnitude of startle to pulse without a preceding prepulse)].</p>c<p>Overall signal/noise discrimination (d′).</p>d<p>Three-digit d′.</p>e<p>Four-digit d′.</p>f<p>After each sequence, the participant is asked to recall the numbers and letters in the same exact order, with no reordering of the stimuli. The number of digits and letters increases by one on each trial, from one up to a maximum length of 8 stimuli. Three sequences of the same length are presented during each trial. The test is discontinued when the subject fails three consecutive sequences of the same length. The score is the total number of correctly recalled sequences.</p>g<p>After each sequence, the participant is asked to repeat the numbers in ascending order first and then the letters in alphabetical order.</p>h<p>Trials 1–5 Free Recall Correct.</p>i<p>Total semantic clustering scores on trials 1–5.</p>j<p>The number of correct responses standardized to a z-score based on the COGS community control subjects.</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies