Faculty Bibliography

Cognitive impairment is a common feature of the major psychotic disorders, with deficits often present in at risk individuals and unaffected first-degree relatives. Previous studies have suggested that polygenic risk scores (PRS) for schizophrenia (SCZ) are associated with cognitive deficits, but there has been little examination of this association in longitudinal datasets, or comparison with other disorders. We used mixed models to study the association between PRS for 4 adult onset psychiatric disorders with cross-sectional cognitive performance and longitudinal cognitive decline in 8616 older adults from the Health and Retirement Study (HRS), followed for an average of 10 years. PRS were computed for SCZ, bipolar disorder (BD), Major Depressive Disorder (MDD), and Alzheimer's disease (ALZ). SCZ PRS associated with decreased cognitive function (z = -3.00, P = .001, ΔR (2) = 0.04%), which was largely driven by an association with impaired attention and orientation (z = -3.33, P = 4.3×10(-4), ΔR (2) = 0.08%). We found no effect of BD or MDD PRS on cognition, in contrast to a robust effect of the APOE4/TOMM40 locus (z = -5.05, P = 2.2×10(-7), ΔR (2) = 0.36%), which was primarily associated with impaired verbal memory (z = -5.15, P = 1.3×10(-7), ΔR (2) = 0.21%). APOE4/TOMM40 locus and the ALZ PRS, but not the PRS for SCZ, were associated with greater cognitive decline. In summary, using a large, representative sample of older adults, we found evidence for different degrees of association between polygenic risk for SCZ and genetic risk factors for ALZ on cognitive function and decline, highlighting potential differences in the pathophysiology of cognitive deficits seen in SCZ and ALZ.

BACKGROUND:Distinguishing bipolar disorder (BP) from major depressive disorder (MDD) has important relevance for prognosis and treatment. Prior studies have identified clinical features that differ between these two diseases but have been limited by heterogeneity and lack of replication. We sought to identify depression-related features that distinguish BP from MDD in large samples with replication. METHOD/METHODS:Using a large, opportunistically ascertained collection of subjects with BP and MDD we selected 34 depression-related clinical features to test across the diagnostic categories in an initial discovery dataset consisting of 1228 subjects (386 BPI, 158 BPII and 684 MDD). Features significantly associated with BP were tested in an independent sample of 1000 BPI cases and 1000 MDD cases for classifying ability in receiver operating characteristic (ROC) analysis. RESULTS:Seven clinical features showed significant association with BPI compared with MDD: delusions, psychomotor retardation, incapacitation, greater number of mixed symptoms, greater number of episodes, shorter episode length, and a history of experiencing a high after depression treatment. ROC analyses of a model including these seven factors showed significant evidence for discrimination between BPI and MDD in an independent dataset (area under the curve = 0.83). Only two features (number of mixed symptoms, and feeling high after an antidepressant) showed an association with BPII versus MDD. CONCLUSIONS:Our study suggests that clinical features distinguishing depression in BPI versus MDD have important classification potential for clinical practice, and should also be incorporated as 'baseline' features in the evaluation of novel diagnostic biomarkers.

Domestic dog breeds have undergone intense selection for a variety of morphologic features, including size. Among small-dog breeds, defined as those averaging less than ~15 in. at the withers, there remains still considerable variation in body size. Yet essentially all such dogs are fixed for the same allele at the insulin-like growth factor 1 gene, which we and others previously found to be a size locus of large effect. In this study we sought to identify additional genes that contribute to tiny size in dogs using an association scan with the single nucleotide polymorphism (SNP) dataset CanMap, in which 915 purebred dogs were genotyped at 60,968 SNP markers. Our strongest association for tiny size (defined as breed-average height not more than 10 in. at the withers) was on canine chromosome 3 (p = 1.9 × 10(-70)). Fine mapping revealed a nonsynonymous SNP at chr3:44,706,389 that changes a highly conserved arginine at amino acid 204 to histidine in the insulin-like growth factor 1 receptor (IGF1R). This mutation is predicted to prevent formation of several hydrogen bonds within the cysteine-rich domain of the receptor's ligand-binding extracellular subunit. Nine of 13 tiny dog breeds carry the mutation and many dogs are homozygous for it. This work underscores the central importance of the IGF1 pathway in controlling the tremendous size diversity of dogs.