Person:

Handsaker, Robert

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia’s association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals affected with schizophrenia.

Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces by utilizing the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning four million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified eight large novel inter-chromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed in RNA and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies.

Background: Depressive disorders are the second-leading cause of global disability, and an area of increasing focus in international health efforts. We describe a community health worker (CHW) program rolled out in a stepped-wedge design during the course of routine patient care to 74 patients with depression in 4 communities in rural Mexico. Methods: We used random effects models to calculate the change in Patient Health Questionnaire-9 (PHQ-9) scores, an internationally validated measure of depression, before and after the CHW program was introduced. As a secondary outcome, we also examined the change pre- and post-intervention in the proportion of patients who had a mean of at least one visit per month for depression follow-up, in accordance with clinic visit guidelines. Results: In multivariate mixed-effects regression, the introduction of the CHW program was associated with a 2.1-point decrease in PHQ-9 score (95% CI: -3.7 to -0.50) followed by a decrease in PHQ-9 score of 0.19 points per month (95% CI: -0.41 to 0.02), beyond standard care. There was strong evidence that patients were far more likely to attend a mean of at least one visit per month (adjusted OR = 8.5, 95% CI: 7.2 to 9.7) after the intervention was introduced in a community. Conclusions: Our results suggest an association between the introduction of a CHW program and improved depression outcomes and appointment adherence. Our findings are limited by missing data. Future research is necessary to develop evidence-based mental health interventions implementable in low-resource settings.

Disruptive and damaging ultra-rare variants (URVs) in highly constrained (HC) genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE; −3.1 months; P-value=3.3×10−8). This effect was stronger among high brain-expressed genes and explained more YOE variance than pathogenic copy number variation, but less than common variants. Disruptive and damaging URVs in HC genes influence the determinants of YOE in the general population.

Thousands of genome segments appear to be present in widely varying copy number in different human genomes. We developed ways to use increasingly abundant whole genome sequence data to identify the copy numbers, alleles and haplotypes present at most large, multi-allelic CNVs (mCNVs). We analyzed 849 genomes sequenced by the 1000 Genomes Project to identify most large (>5 kb) mCNVs, including 3,878 duplications, of which 1,356 appear to have three or more segregating alleles. We find that mCNVs give rise to most human gene-dosage variation – exceeding sevenfold the contribution of deletions and biallelic duplications – and that this variation in gene dosage generates abundant variation in gene expression. We describe “runaway duplication haplotypes” in which genes, including HPR and ORM1, have mutated to high copy number on specific haplotypes. We describe partially successful initial strategies for analyzing mCNVs via imputation and provide an initial data resource to support such analyses.