Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

See related commentary by Kanis, page [1829][1]

Since the publication of the Osteoporosis Canada guidelines in 2002, there has been a paradigm shift in the prevention and treatment of osteoporosis and fractures. [1][2],[2][3] The focus now is on preventing fragility fractures and their negative

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2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary

This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

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The human obesity gene map: the 2005 update.

This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single-gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity-related phenotypes from 50 genome-wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http://obesitygene.pbrc.edu.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/oby.2005.50

The human obesity gene map: the 2004 update.

Estrogens play a fundamental role in the physiology of the reproductive, cardiovascular, skeletal, and central nervous systems. In this report, we review the literature in both rodents and humans on the role of estrogens and their receptors in the control of energy homeostasis and glucose metabolism in health and metabolic diseases. Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution. Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation. Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival. Estrogen deficiency promotes metabolic dysfunction predisposing to obesity, the metabolic syndrome, and type 2 diabetes. We also discuss the effect of selective estrogen receptor modulators on metabolic disorders.

The role of estrogens in control of energy balance and glucose homeostasis.

Background: Hormone replacement therapy (HRT), the mainstay of osteoporosis prevention, is limited because of dose-related risks, side effects, and patient acceptance. The bone-sparing efficacy and tolerability of the lowest available doses of HRT have not been adequately studied in elderly women. Objective: To determine the bone-sparing effect of continuous low-dose HRT in elderly women. Design: Randomized, double-blind, placebo-controlled trial. Setting: University osteoporosis research and clinical center. Patients: 128 healthy white women (age > 65 years) with low bone mass recruited by word of mouth and by local advertisement. The principal eligibility criterion was spinal bone mineral density of 0.90 g/cm 2 or less. Intervention: Continuous therapy with conjugated equine estrogen, 0.3 mg/d, and medroxyprogesterone, 2.5 mg/d, or matching placebo. Sufficient calcium supplementation was given to bring all calcium intakes above 1000 mg/d in both groups; supplemental oral 25-hydroxyvitamin D was given to maintain serum 25-hydroxyvitamin D levels of at least 75 nmol/L in both groups. Measurements: Bone mineral density of the spine, hip, total body, and forearm; serum total alkaline phosphatase and serum osteocalcin levels at 6-month intervals; and 24-hour urine creatinine and hydroxyproline excretion at baseline, 12 months, and 42 months. Results: During 3.5 years of observation, spinal bone mineral density increased by 3.5% (P < 0.001) in an intention-to-treat analysis and by 5.2% among patients with greater than 90% adherence to therapy. Significant increases were seen in total-body and forearm bone density (P < 0.01). Symptoms related to HRT (breast tenderness, spotting, pelvic discomfort, and mood changes) were mild and short-lived. Conclusions: Continuous low-dose HRT with conjugated equine estrogen and oral medroxyprogesterone combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other, higher-dose HRT regimens in elderly women. This combination is well tolerated by most patients.

The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial.

Clinical trials of treatment agents impose strict and often necessary inclusion and exclusion criteria, while patients presenting to physicians for treatment frequently exhibit complicating features that would have excluded them from entry into study. To quantify the degree of discordance between ordinary patients and study subjects, a retrospective chart review was carried out of all new patients with osteoporosis seen in an academic medical center within a consecutive 40-month period, meeting clinical treatment criteria. Each patient chart was reviewed for the inclusion and exclusion criteria of four large, multicenter study protocols. There were 120 consecutive female patients seeking health care, with bone density T-scores below −2.0 and/or with one or more low-trauma fractures. The four trials would have accepted 4, 5, 25 and 8 of our 120 patients. The trial with the most liberal inclusion criteria would have taken only 21% of the total. Principal reasons for ineligibility were comorbidity, prior treatment with bone-active agents, and current therapy with glucocorticoids, anticoagulants and anticonvulsants. Some of these exclusions inevitably reflect the patient mix of a referral center; nevertheless, comorbidity and its therapy are common in the age range in which osteoporosis is prevalent and would, therefore, be expected to be present in patients in general medical practice as well. Thus a large fraction, perhaps the majority, of patients with diagnoses of osteoporosis who are candidates for treatment by their physicians, are not eligible for entry into typical treatment trials. The results of such trials may, therefore, have uncertain applicability to types of patients excluded, both for safety and for efficacy.

Study Subjects and Ordinary Patients

Several lines of evidence suggest the importance of the estrogen receptor (ER) in determining body mass index (BMI). Our purpose was to investigate whether genetic polymorphisms at the restriction enzyme PvuII site of the ER-α gene locus are associated with BMI variation. Data on BMI, age, and ER-α genotypes were obtained from 108 healthy midwestern U.S. postmenopausal Caucasian women. The study subjects were unrelated and aged 65 yr and over (mean age ± sd, 73.4 ± 5.1 yr), with an average BMI of 25.25 (sd, 4.04). The ER-α genotypes were obtained by PCR followed by restriction enzyme PvuII digestion. We found that in our study subjects the ER-α genotypes are significantly associated with BMI (by ANOVA, P = 0.04), explaining about 6.2% of the BMI variation in our study sample. The allelic effects of this locus on BMI are approximately additive. In our sample, individuals of the PP and Pp genotypes have, respectively, 11.4% and 4.8% higher BMI than individuals of the pp genotype. There is a significant ER-α...

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Rachel Dowd

Papers

The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial.

Study Subjects and Ordinary Patients

Association of estrogen receptor-α genotypes with body mass index in normal healthy postmenopausal caucasian women

Patient care of osteoporosis.