There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

/pdf/genome-wide-association-study-of-14-000-cases-of-seven-5ay7q0q3vy.pdf

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

A b s t r ac t Background Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods We first identified chromosomal loci that were strongly associated with coronary ar- tery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI (Myocardial Infarction) Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single- nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

/pdf/genomewide-association-analysis-of-coronary-artery-disease-6c1xcn346m.pdf

Genomewide association analysis of coronary artery disease.

ContextLysosomal storage disorders represent a group of at
least 41 genetically distinct, biochemically related, inherited
diseases. Individually, these disorders are considered rare, although
high prevalence values have been reported in some populations. These
disorders are devastating for individuals and their families and result
in considerable use of resources from health care systems; however, the
magnitude of the problem is not well defined. To date, no comprehensive
study has been performed on the prevalence of these disorders as a
group.ObjectiveTo determine the prevalence of lysosomal storage
disorders individually and as a group in the Australian population.DesignRetrospective case studies.SettingAustralia, from January 1, 1980, through December 31,
1996.Main Outcome MeasureEnzymatic diagnosis of a lysosomal storage
disorder.ResultsTwenty-seven different lysosomal storage disorders were
diagnosed in 545 individuals. The prevalence ranged from 1 per
57,000 live births for Gaucher disease to 1 per 4.2 million live
births for sialidosis. Eighteen of 27 disorders had more than 10
diagnosed cases. As a group of disorders, the combined prevalence was 1
per 7700 live births. There was no significant increase in the rate of
either clinical diagnoses or prenatal diagnoses of lysosomal storage
disorders during the study period.ConclusionsIndividually, lysosomal storage disorders are rare
genetic diseases. However, as a group, they are relatively common and
represent an important health problem in Australia.

https://jamanetwork.com/journals/jama/articlepdf/188380/JOC80368.pdf

Prevalence of lysosomal storage disorders.

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

Protein therapeutics: a summary and pharmacological classification

This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting

The Metabolic Basis Of Inherited Disease.

Background: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an autosomal recessive disorder caused by a defect in the glycine cleavage system. NKH is classically associated with neonatal apnea, lethargy, hypotonia, and seizures, followed by severe psychomotor retardation in those who survive. Methods: To determine the natural history of NKH, the authors mailed a 44-question survey to 170 households in the International NKH Family Network. Results: Data for 65 patients (36 boys, 29 girls) were collected from 58 families. One-third of the subjects died; 8 girls died during the neonatal period, and 14 patients died thereafter (2 girls, 12 boys). Median age of death for boys was 2.6 years vs p = 0.02). Mean birth weight and length, occipitofrontal circumference, and gestation duration were normal. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. Interestingly, three NKH patients never developed seizures. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living ≥3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family. Conclusions: This study reveals a striking and unexpected gender difference in mortality and developmental progress. Of the two-thirds of nonketotic hyperglycinemia patients surviving the newborn period, up to 20% (mostly boys) may learn to walk and communicate by saying or signing words.

Natural history of nonketotic hyperglycinemia in 65 patients

Nonketotic Hyperglycinemia (Glycine Encephalopathy): Laboratory Diagnosis

Glycine concentrations were measured in plasma and cerebrospinal fluid of five patients in different types of hyperglycinemia to determine why severe neurologic deterioration is confined to the so-called nonketotic form of hyperglycinemia. Glycine content and glycine-cleavage enzyme activity were also determined in brain obtained in autopsy from three of these patients. Spinal-fluid glycine concentrations were 15 to 30 times above normal in patients with nonketotic hyperglycinemia, but were normal in those with hyperglycinemias of undetermined type who had comparable elevations of plasma glycine. Glycine content was two to four times above normal in several brain regions, and brain glycine cleavage enzyme activity was absent in two patients dying of nonketotic hyperglycinemia. By contrast, glycine content was normal and glycine cleavage activity present in the brain of an infant who died of hyperglycinemia of unknown cause. These results suggest that elevated glycine levels may be harmless in blood, but lethal in brain.

Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain.

~Department of Paediatrics, Alberta Children's Hospital Research Centre, University of Calgary, 1820 Richmond Road SW, Calgary, Alberta T2T 5C7, Canada 2Department of Paediatrics, Biochemical Diseases Laboratory, British Columbia's Children's Hospital, University of British Columbia, Vancouver, BC V6H 3V4, Canada 3B. C. Health Surveillance Registry, Division of Vital Statistics Government of British Columbia, Vancouver, BC V6Z 2C5, Canada

An update on the frequency of mucopolysaccharide syndromes in British Columbia.

L-methionine 10 mMole/Kg. per day administered orally to guinea pigs leads to a state characterized early by fatty liver, hypoglycemia and aminoacidemia and later by hypothermia, profound hypoglycemia and death within 60 hours. Paralleling the development of this state is a progressive fall in hepatic ATP probably caused by binding of available hepatic ATP to methionine, thus forming increasing and substantial amounts of hepatocellular S-adenosylmethionine and S-adenosylhomocysteine. In support of the concept that the biochemical changes induced by methionine intoxication are mediated through an hepatic ATP insufficiency is the finding that adenine, administered to intoxicated animals completely reverses the hypoglycemic effects of methionine. The possibility that a similar mechanism of intoxication occurs in human methionine ingestion and hypermethioninemic states is discussed.

Derek A. Applegarth

Papers

Natural history of nonketotic hyperglycinemia in 65 patients

Nonketotic Hyperglycinemia (Glycine Encephalopathy): Laboratory Diagnosis

Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain.

An update on the frequency of mucopolysaccharide syndromes in British Columbia.

Pathogenesis of methionine-induced toxicity☆