The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

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NATURE GENETICS VOLUME 36 | NUMBER 3 | MARCH 2004 233Cardiovascular diseases (CVD) are the leading causes of death and disability in the developed world 1 , with an increasing prevalence due to the aging of the population and the obesity epidemic. More than 1 million deaths in the US alone were caused by myocardial infarction and stroke in 2003 (ref. 2). Some of the processes underlying myocardial infarction are now understood: it is generally attributed to atherosclerosis with arterial wall inflammation that ultimately leads to plaque rupture, fissure or erosion 3,4 . This process is known to involve diapedesis of monocytes across the endothelial barrier; activation of neutrophils, macrophage cells and platelets; and release of a variety of cytokines and chemokines 5,6 , but the genetic basis of the process has not yet been deciphered. Two different approaches have been used to search for genes associated with myocardial infarction. SNPs in candidate genes have been tested for association and have, in general, not been replicated or confer only a modest risk of myocardial infarction. Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect 7-9 . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 . This is an interesting cause of myocardial infarction, but the prevalence of this or other mutations in MEF2A outside this family remains to be determined.Here we report a genome-wide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction. Through suggestive linkage to a locus on chromosome 13q12-13, we identified the gene (ALOX5AP) encoding FLAP and found that a four-SNP haplotype in the gene confers a nearly two times greater risk of myocardial infarction and stroke. FLAP is a regulator 15 of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model 16 and in human studies 17,18 . Males had the strongest association to the at-risk haplotype, and male carriers of the at-risk haplotype also had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction. We confirmed the association of ALOX5AP with myocardial infarction in an independent cohort of British individuals with another haplotype. These results indicate that ALOX5AP is the first specific gene isolated that confers substantial population-attributable risk (PAR) of the complex traits of both myocardial infarction and stroke. We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13....

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.