Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.

We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.

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.

A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

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....

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.

Eight regions of the genome (PARK1-8) have been implicated in autosomal dominant and autosomal recessive forms of early-onset Parkinson's disease. These forms constitute a few of all cases. However, except for a haplotype in six families (PARK3), no study has successfully mapped a gene or described mutations that contribute to the common late-onset Parkinson's disease. Some have even suggested that a genetic component does not exist. We cross-matched our nationwide genealogy database with a population-based list of Icelandic Parkinson's disease patients to search for families with more than one patient. We performed a genomewide scan on 117 patients and 168 of their unaffected relatives within 51 families using 781 microsatellite markers. Allele-sharing, model-independent analysis of the results showed linkage to a region on chromosome 1p32 with a logarithm of odds score of 3.9 (Z(lr) = 4.2). By increasing the information content with additional microsatellite markers in this region, we found that the logarithm of odds score increased to 4.9 (Z(lr) = 4.8). This result corresponds to an unadjusted p value of 1.0 x 10(-6) and p < 0.005 after adjusting for a genomewide search. We designate this region PARK10. We therefore have successfully mapped, to genomewide significance, a susceptibility gene for late-onset Parkinson's disease using multiple families drawn across a whole population. Identification of the susceptibility gene in this region may pave the way for a better understanding of the disease process, which, in turn, may lead to improved diagnostics and therapeutics.