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Article ; Online: Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium.

Siland, J E / Geelhoed, B / Roselli, C / Wang, B / Lin, H J / Weiss, S / Trompet, S / van den Berg, M E / Soliman, E Z / Chen, L Y / Ford, I / Jukema, J W / Macfarlane, P W / Kornej, J / Lin, H / Lunetta, K L / Kavousi, M / Kors, J A / Ikram, M A /

Guo, X / Yao, J / Dörr, M / Felix, S B / Völker, U / Sotoodehnia, N / Arking, D E / Stricker, B H / Heckbert, S R / Lubitz, S A / Benjamin, E J / Alonso, A / Ellinor, P T / van der Harst, P / Rienstra, M

PloS one

2022 Volume 17, Issue 5, Page(s) e0268768

Abstract: Background: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF ...

Abstract	Background: Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results: Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65-75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94-0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions: For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.
MeSH term(s)	Aged ; Atrial Fibrillation ; Electrocardiography ; Female ; Heart Rate/genetics ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Random Allocation ; Risk Factors
Language	English
Publishing date	2022-05-20
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0268768
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Article: Strategy for mapping minor histocompatibility genes involved in graft-versus-host disease: a novel application of discordant sib pair methodology.

Lunetta, K L / Rogus, J J

Genetic epidemiology

1998 Volume 15, Issue 6, Page(s) 595–607

Abstract: We introduce a novel application for linkage analysis: using bone marrow donor-recipient sib pairs to search for genes influential in graft-versus-host disease (GVHD), a major cause of morbidity and mortality following allogeneic bone marrow ... ...

Abstract	We introduce a novel application for linkage analysis: using bone marrow donor-recipient sib pairs to search for genes influential in graft-versus-host disease (GVHD), a major cause of morbidity and mortality following allogeneic bone marrow transplantation. In particular, we show that transplant sib pairs in which the recipient developed severe GVHD can be used to map genes in the same way as traditional discordant (affected/unaffected) sib pairs (DSPs). For a plausible GVHD model, we demonstrate that the transplant/discordant sib pair analog of the "possible triangle test" [Holmans (1993) Am J Hum Genet 52:362-374] has similar power to that of the simpler "restricted test" proposed by Risch [(1990b) Am J Hum Genet 46:229-241; (1992) Am J Hum Genet 51:673-675]. Moreover, we show that the restricted test has superior power in much of the DSP possible triangle and significantly inferior power in only a small region. Thus, we conclude that the restricted test is preferable for localizing genes with transplant/discordant sib pairs. Finally, we examine the effects of heterogeneity on the power to detect GVHD loci and demonstrate the gain in efficiency by dividing the sample into genetically more homogeneous subgroups.
MeSH term(s)	Chromosome Mapping/methods ; Genetic Heterogeneity ; Genetic Linkage/genetics ; Graft vs Host Disease/genetics ; Graft vs Host Disease/immunology ; Humans ; Likelihood Functions ; Lod Score ; Minor Histocompatibility Antigens/genetics ; Models, Genetic ; Pedigree ; Reproducibility of Results
Chemical Substances	Minor Histocompatibility Antigens
Language	English
Publishing date	1998
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/(SICI)1098-2272(1998)15:6<595::AID-GEPI4>3.0.CO;2-4
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Article ; Online: The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study.

Travison, T G / Zhuang, W V / Lunetta, K L / Karasik, D / Bhasin, S / Kiel, D P / Coviello, A D / Murabito, J M

Clinical endocrinology

2013 Volume 80, Issue 2, Page(s) 277–282

Abstract: Objective: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, ...

Abstract	Objective: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. Design: Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. Participants: A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. Measurements: Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. Results: Age-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG ) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48). Conclusion: Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.
MeSH term(s)	Adult ; Chromatography, Liquid ; Cross-Sectional Studies ; Estradiol/blood ; Estrone/blood ; Family Health ; Fluoroimmunoassay ; Genes, Y-Linked/genetics ; Genetic Association Studies/methods ; Humans ; Male ; Middle Aged ; Sex Hormone-Binding Globulin/metabolism ; Tandem Mass Spectrometry ; Testosterone/blood
Chemical Substances	Sex Hormone-Binding Globulin ; Estrone (2DI9HA706A) ; Testosterone (3XMK78S47O) ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2013-06-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.12260
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Article ; Online: Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

Sarnowski, C / Cousminer, D L / Franceschini, N / Raffield, L M / Jia, G / Fernández-Rhodes, L / Grant, S F A / Hakonarson, H / Lange, L A / Long, J / Sofer, T / Tao, R / Wallace, R B / Wong, Q / Zirpoli, G / Boerwinkle, E / Bradfield, J P / Correa, A / Kooperberg, C L /

North, K E / Palmer, J R / Zemel, B S / Zheng, W / Murabito, J M / Lunetta, K L

Human reproduction (Oxford, England)

2021 Volume 36, Issue 7, Page(s) 1999–2010

Abstract: Study question: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world ...

Abstract	Study question: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? Summary answer: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. What is known already: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. Study design, size, duration: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. Participants/materials, setting, methods: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. Main results and the role of chance: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. Large scale data: N/A. Limitations, reasons for caution: Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. Wider implications of the findings: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. Study funding/competing interest(s): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.
MeSH term(s)	Adolescent ; Cohort Studies ; Ethnicity ; Female ; Genome-Wide Association Study ; Humans ; Menarche/genetics ; Polymorphism, Single Nucleotide
Language	English
Publishing date	2021-05-19
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural
ZDB-ID	632776-x
ISSN	1460-2350 ; 0268-1161 ; 1477-741X
ISSN (online)	1460-2350
ISSN	0268-1161 ; 1477-741X
DOI	10.1093/humrep/deab086
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Article: On the validity of the TDT test in the presence of comorbidity and ascertainment bias.

Robins, J M / Smoller, J W / Lunetta, K L

Genetic epidemiology

2001 Volume 21, Issue 4, Page(s) 326–336

Abstract: Comorbidity, the association of two disorders, occurs commonly with complex diseases. In this paper, we investigate the effects of both true (within-family) comorbidity and spurious comorbidity due to ascertainment bias on the validity of both the ... ...

Abstract	Comorbidity, the association of two disorders, occurs commonly with complex diseases. In this paper, we investigate the effects of both true (within-family) comorbidity and spurious comorbidity due to ascertainment bias on the validity of both the parental and sibling control transmission/disequilibrium test. Specifically, we consider settings in which a candidate gene is unlinked to the target phenotype but is in linkage disequilibrium with a comorbid phenotype. We derive conditions under which the presence of true and/or spurious comorbidity will result in an artificial correlation between the target phenotype and the candidate gene.
MeSH term(s)	Bias ; Case-Control Studies ; Causality ; Chromosome Mapping/methods ; Chromosome Mapping/standards ; Comorbidity ; Data Interpretation, Statistical ; Heterozygote ; Homozygote ; Humans ; Linkage Disequilibrium/genetics ; Models, Genetic ; Phenotype ; Regression Analysis ; Sensitivity and Specificity ; Statistics, Nonparametric
Language	English
Publishing date	2001-12
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Validation Studies
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.1038
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Article: Multipoint radiation hybrid mapping: comparison of methods, sample size requirements, and optimal study characteristics.

Lunetta, K L / Boehnke, M

Genomics

1994 Volume 21, Issue 1, Page(s) 92–103

Abstract: There are several statistical methods available for analyzing radiation hybrid (RH) data, but little is known about the ordering accuracy we can expect under common study conditions. Using analytic methods and computer simulation, we compared the ... ...

Abstract	There are several statistical methods available for analyzing radiation hybrid (RH) data, but little is known about the ordering accuracy we can expect under common study conditions. Using analytic methods and computer simulation, we compared the ordering accuracy of three multipoint statistical methods: minimum breaks (MB), maximum likelihood (ML), and maximum posterior probability (PP). For 8, 12, and 16 markers and all combinations of numbers of hybrids, retention patterns, and marker spacings considered, the probabilities that the true order is identified as the best order were considerably higher with the ML and PP methods than with the MB method. ML and PP performed similarly, but PP tended to give slightly greater support for the best order than did ML. Our results can be used as guidelines for determining sample size requirements and optimal marker spacing for future RH mapping experiments. For equally spaced markers, intermarker spacing of 30 to 50 cR gave the highest probability of correctly ordering all the markers. For randomly spaced markers, 10-20 cR average intermarker spacing resulted in the highest proportion of markers being placed in a 1000:1 framework map. Assuming equal retention in the analysis when a centromeric model would be more appropriate did not affect the ability of the ML method to accurately order the markers, but did influence the distance estimates obtained.
MeSH term(s)	Animals ; Bayes Theorem ; Cell Fusion ; Centromere ; Chromosome Mapping/methods ; Chromosomes, Human/radiation effects ; Chromosomes, Human/ultrastructure ; Culture Media ; Genetic Markers ; Humans ; Hybrid Cells/radiation effects ; Hypoxanthine Phosphoribosyltransferase/deficiency ; Likelihood Functions ; Rodentia ; Selection, Genetic
Chemical Substances	Culture Media ; Genetic Markers ; Hypoxanthine Phosphoribosyltransferase (EC 2.4.2.8)
Language	English
Publishing date	1994-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	356334-0
ISSN	1089-8646 ; 0888-7543
ISSN (online)	1089-8646
ISSN	0888-7543
DOI	10.1006/geno.1994.1229
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Zs.A 2367: Show issues

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Article: Implications of comorbidity and ascertainment bias for identifying disease genes.

Smoller, J W / Lunetta, K L / Robins, J

American journal of medical genetics

2000 Volume 96, Issue 6, Page(s) 817–822

Abstract: Comorbidity, the co-occurrence of disorders, is frequently observed to occur at higher rates in clinically ascertained samples than in population-based samples. An explanation for this finding is that subjects suffering from multiple illnesses are more ... ...

Abstract	Comorbidity, the co-occurrence of disorders, is frequently observed to occur at higher rates in clinically ascertained samples than in population-based samples. An explanation for this finding is that subjects suffering from multiple illnesses are more likely to seek medical care and receive a diagnostic evaluation. We refer to the component of the comorbidity between illnesses due to such ascertainment bias as "spurious comorbidity." When spurious comorbidity is present, an apparent association between a candidate locus and the phenotype of interest may actually be attributable to an association between the locus and a comorbid phenotype. This phenomenon, which we call "spurious comorbidity bias," could thus produce misleading association findings. In this article, we describe this phenomenon and demonstrate that it may produce marked bias in the conclusions of family-based association studies. Because of the extremely high rates of comorbidity among psychiatric disorders in clinical samples, this problem may be particularly salient for genetic studies of neuropsychiatric disorders. We conclude that ascertainment bias may contribute to the frequent difficulty in replicating candidate gene study findings in psychiatry. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:817-822, 2000.
MeSH term(s)	Alleles ; Bias ; Comorbidity ; Depressive Disorder/genetics ; Gene Frequency ; Genetic Predisposition to Disease/genetics ; Humans ; Models, Genetic ; Penetrance ; Phenotype
Language	English
Publishing date	2000-02-23
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	133387-2
ISSN	0148-7299
ISSN	0148-7299
DOI	10.1002/1096-8628(20001204)96:6<817::aid-ajmg25>3.0.co;2-a
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Article ; Online: Head circumference, atrophy, and cognition: implications for brain reserve in Alzheimer disease.

Perneczky, R / Wagenpfeil, S / Lunetta, K L / Cupples, L A / Green, R C / Decarli, C / Farrer, L A / Kurz, A

Neurology

2010 Volume 75, Issue 2, Page(s) 137–142

Abstract: Background: Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference.: ... ...

Abstract	Background: Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference. Methods: A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition. Results: There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference. Conclusion: This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.
MeSH term(s)	Aged ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Apolipoproteins E/genetics ; Atrophy/pathology ; Brain/pathology ; Cephalometry ; Cross-Sectional Studies ; Female ; Head/pathology ; Humans ; Male ; Neuropsychological Tests ; Regression Analysis
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2010-07-12
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0b013e3181e7ca97
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Article ; Online: Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Longchamps, R J / Yang, S Y / Castellani, C A / Shi, W / Lane, J / Grove, M L / Bartz, T M / Sarnowski, C / Liu, C / Burrows, K / Guyatt, A L / Gaunt, T R / Kacprowski, T / Yang, J / De Jager, P L / Yu, L / Bergman, A / Xia, R / Fornage, M /

Feitosa, M F / Wojczynski, M K / Kraja, A T / Province, M A / Amin, N / Rivadeneira, F / Tiemeier, H / Uitterlinden, A G / Broer, L / Van Meurs, J B J / Van Duijn, C M / Raffield, L M / Lange, L / Rich, S S / Lemaitre, R N / Goodarzi, M O / Sitlani, C M / Mak, A C Y / Bennett, D A / Rodriguez, S / Murabito, J M / Lunetta, K L / Sotoodehnia, N / Atzmon, G / Ye, K / Barzilai, N / Brody, J A / Psaty, B M / Taylor, K D / Rotter, J I / Boerwinkle, E / Pankratz, N / Arking, D E

Human genetics

2021 Volume 141, Issue 1, Page(s) 127–146

Abstract: Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial ... ...

Abstract	Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10
MeSH term(s)	Aged ; Cell Proliferation ; DNA Copy Number Variations ; DNA, Mitochondrial ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Male ; Megakaryocytes/physiology ; Middle Aged ; Mitochondria/genetics ; Nucleotides/metabolism ; Phenotype ; Platelet Activation ; Polymorphism, Single Nucleotide
Chemical Substances	DNA, Mitochondrial ; Nucleotides
Language	English
Publishing date	2021-12-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-021-02394-w
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Article: Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions.

Lunetta, K L / Faraone, S V / Biederman, J / Laird, N M

American journal of human genetics

2000 Volume 66, Issue 2, Page(s) 605–614

Abstract: We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a ... ...

Abstract	We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a phenotype and any number of predictors. We then construct a score statistic, using likelihoods for the distribution of phenotype, given genotype. The distribution of the score is computed as a function of offspring genotypes, conditional on parental genotypes and trait values for offspring and parents. This approach provides a natural extension of the transmission/disequilibrium test to any phenotype and to multiple genes or environmental factors and allows the study of gene-gene and gene-environment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one or more nuisance parameters. We suggest two approaches for obtaining parameter estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter and using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how covariates and gene-environment and gene-gene interactions can be incorporated.
MeSH term(s)	Alleles ; Attention Deficit Disorder with Hyperactivity/genetics ; Attention Deficit Disorder with Hyperactivity/physiopathology ; Carrier Proteins/genetics ; Chromosome Mapping/methods ; Chromosome Mapping/statistics & numerical data ; Dopamine Plasma Membrane Transport Proteins ; Environment ; Female ; Genetic Linkage/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Genotype ; Humans ; Male ; Membrane Glycoproteins ; Membrane Transport Proteins ; Models, Genetic ; Nerve Tissue Proteins ; Nuclear Family ; Phenotype ; Receptors, Dopamine D2/genetics ; Receptors, Dopamine D4 ; Sex Factors
Chemical Substances	Carrier Proteins ; DRD4 protein, human ; Dopamine Plasma Membrane Transport Proteins ; Membrane Glycoproteins ; Membrane Transport Proteins ; Nerve Tissue Proteins ; Receptors, Dopamine D2 ; Receptors, Dopamine D4 (137750-34-6)
Language	English
Publishing date	2000-02
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1086/302782
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