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Advances
in
Genetics, Volume 62

Serial Editors
Jeffrey C. Hall
Orono, Maine
Jay C. Dunlap
Hanover, New Hampshire
Theodore Friedmann
La Jolla, California
Veronica van Heyningen
Edinburgh, United Kingdom
Academic Press is an imprint of Elsevier
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ISBN: 978-0-12-374443-2
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08 09 10 11 12 10 9 8 7 6 5 4 3 2 1
 CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

Larry D. Atwood (33) Department of Neurology, Boston University School of

Medicine, Boston, Massachusetts 02118; Department of Biostatistics,
Boston University School of Public Health, Boston, Massachusetts
02118
Emelia J. Benjamin (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702; Department of Cardiology, Boston University
School of Medicine, Boston, Massachusetts 02118; Department of
Epidemiology, Boston University School of Public Health, Boston,
Massachusetts 02118
Stephen Chanock (1) Laboratory of Translation Genomics, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National Insti-
tutes of Health, Bethesda, Maryland 20892; Core Genotyping Facility,
Advanced Technology Center, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland 20892
L. Adrienne Cupples (33) Department of Biostatistics, Boston University
School of Public Health, Boston, Massachusetts 02118
Ralph B. D’Agostino (33) Department of Biostatistics, Boston University
School of Public Health, Boston, Massachusetts 02118; NHLBI’s
Framingham Heart Study, Framingham, Massachusetts 01702
Caroline S. Fox (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702
Diddahally R. Govindaraju (33) Department of Neurology, Boston University
School of Medicine, Boston, Massachusetts 02118
Jeffrey C. Hall (67) School of Biology and Ecology, University of Maine,
Orono, Maine
William B. Kannel (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702
Andreas E. Kulozik (185) Department for Pediatric Oncology, Hematology and
Immunology, University Hospital Heidelberg and Molecular Medicine
Partnership Unit, University of Heidelberg and European Molecular
Biology Laboratory, Im Neuenheimer Feld 156, 69120 Heidelberg,
Germany

vii
viii Contributors

Marty Larson (33) NHLBI’s Framingham Heart Study, Framingham,

Massachusetts 01702
Daniel Levy (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702
Joanne Murabito (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702; Section of General Internal Medicine, Boston
University School of Medicine, Boston, Massachusetts 02118
Gabriele Neu-Yilik (185) Department for Pediatric Oncology, Hematology and
Immunology, University Hospital Heidelberg and Molecular Medicine
Partnership Unit, University of Heidelberg and European Molecular
Biology Laboratory, Im Neuenheimer Feld 156, 69120 Heidelberg,
Germany
Christopher J. O’Donnell (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702
Nick Orr (1) Laboratory of Translation Genomics, Division of Cancer Epidemi-
ology and Genetics, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland 20892
Greta Lee Splansky (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702
Ramachandran S. Vasan (33) NHLBI’s Framingham Heart Study, Framingham,
Massachusetts 01702; Department of Cardiology, Boston University
School of Medicine, Boston, Massachusetts 02118; Department of
Epidemiology, Boston University School of Public Health, Boston,
Massachusetts 02118
Adriana Villella (67) Department of Biology, Brandeis University, Waltham,
Massachusetts
Philip A. Wolf (33) Department of Neurology, Boston University School of
Medicine, Boston, Massachusetts 02118
 1

Common Genetic Variation and

Human Disease
Nick Orr* and Stephen Chanock*,†
*Laboratory of Translation Genomics, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, National Institutes of Health, Bethesda,
Maryland 20892
†Core Genotyping Facility, Advanced Technology Center, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland 20892

I. Introduction
II. Variation in the Human Genome
A. Single-nucleotide polymorphisms
B. Factors influencing SNP frequencies in populations
C. SNPs in health and disease
D. Other categories of genomic variation
III. Utilization of Genetic Variation in Gene Mapping Studies
IV. Mapping Complex Disease Genes Using Association
A. Linkage and association: Out with the old and in with the
new?
B. Genetic association testing: The direct approach
C. Genetic association testing: The indirect approach
D. tagSNPs
E. Quantifying LD in the genome
F. Testing association using haplotypes
V. Genome-wide Association Studies
VI. Study Design and Data Analysis
A. Introduction
B. Type I error and the multiple testing problem
C. Additional sources of error

Advances in Genetics, Vol. 62 0065-2660/08 $35.00

DOI: 10.1016/S0065-2660(08)00601-9
2 Orr and Chanock

VII. Significance for Public Health

VIII. Concluding Remarks
References

ABSTRACT

The landscape of human genetics has changed remarkably in a relatively short

space of time. The field has progressed from comparatively small studies of rare
genetic diseases to vast consortia based efforts that target the inherited compo-
nents of common complex diseases and which typically involve thousands of
individual samples. In particular, genome wide association studies have become
possible as a result of a new generation of genotyping platforms. At the time of
writing, these have led to the discovery of more than 150 novel susceptibility loci
across a broad spectrum of diseases, a few in genes with high biological plausibil-
ity but the majority in others that had not been considered candidates. Here, we
provide an overview of the field of complex disease genetics pertaining to
mapping by association and consider the many pitfalls and caveats that have
arisen. ß 2008, Elsevier Inc.

I. INTRODUCTION

Annotation of genetic variation in the human genome coupled with advances in

bioinformatics and technology have significantly changed the landscape of
human genetics. Now geneticists are in a strong position to answer questions
pertaining to the heritability of common conditions. In particular, we are able to
address the contribution of common germ line genetic variation to disease
susceptibility and outcome. In the near future looms the potential to sequence
entire human genomes (Bennett et al., 2005; Binladen et al., 2007; Margulies
et al., 2005), which will yield insights into the significance of less common
genetic variants, perhaps in both common and uncommon diseases.
Successes in the analysis of single-gene disorders using linkage or re-
verse cloning (e.g., hemophilia (Youssoufian et al., 1988), cystic fibrosis (Kerem
et al., 1989), thrombosis (Bertina et al., 1994), and chronic granulomatous
disease (Royer-Pokora et al., 1986) have, until recently, eluded polygenic condi-
tions. The etiology of these diseases may even be further influenced by environ-
mental challenges (Hunter, 2005). Complex diseases do not necessarily follow
traditional patterns of Mendelian inheritance. The identification of disease-
causing genes using conventional linkage-based approaches has been less than
successful because studies do not have the requisite statistical power to detect
 1. Common Genetic Variation and Human Disease 3

low-penetrance, high-frequency alleles. During the course of this review, we will

discuss advances in the approaches for mapping genetic variants that contribute
to complex diseases, particularly those that utilize unrelated subjects. We will
outline the goals and limitations of current procedures and will discuss the recent
successes seen in genome-wide association studies (GWAS). We will also touch
upon issues underlying the pre-GWAS paucity of replicable findings.

II. VARIATION IN THE HUMAN GENOME

A. Single-nucleotide polymorphisms
The human genome is composed of over three billion bases of DNA encoding
between 25,000 and 30,000 genes (International Human Genome Sequencing
Consortium, 2004; Lander et al., 2001; Venter et al., 2001). The most common
form of variation in the genome is the single-nucleotide polymorphism (SNP).
SNPs are DNA variants in which a single nucleotide at a fixed position in the
genome is substituted with another. It has been estimated that there are in excess
of 10 million common [minor allele frequency (MAF)>1%] SNPs within the
genome (Kruglyak and Nickerson, 2001; Reich and Lander, 2001); a small subset
of these likely give rise to the observable phenotypic differences in and between
populations, including disease susceptibility and outcome. One may expect to
observe a single-nucleotide difference between two haploid genomes in the range
of 1 in every 300–1000 base pairs. Although the vast majority of SNPs are shared
between populations (Conrad et al., 2006; Hinds et al., 2005; International
HapMap Consortium, 2005), it is evident that many are specific to populations
or continental grouping of populations that share recent history. In this regard, it
is possible to identify sets of markers that can be used to measure admixture in
populations and that in some circumstances may be utilized to map genes that
could partially account for differences in disease incidence between populations
(Freedman et al., 2006; Patterson et al., 2004; Shriver et al., 2005).

B. Factors influencing SNP frequencies in populations

Because the chemical structure of DNA influences the rate of mutation, there is
bias in the frequency distribution of categories of mutational events. Transitions,
which preserve the class of nucleotide (e.g., purine substituted for purine or
pyrimidine for pyrimidine, A $ G or C $ T, respectively) are more common
than transversions, which result in a switch of a pyrimidine for a purine or purine
for a pyrimidine (A $ C, A $ T, G $ C, or G $ T) (Topal and Fresco, 1976).
New SNPs arise via mutation and with time they either disappear or reach
fixation, replacing the ancestral allele. The time taken for either of these
4 Orr and Chanock

extremes to be reached is proportional to population size; generally, as popula-

tion size increases, so too does the number of generations in which a new SNP
will be observed in its heterozygous state. It is thought that the lifespan of most
SNPs is under the influence of neutral selection because they are inconsequential
with respect to the fitness of an organism.
SNPs that confer a selective advantage among members of a population
may become enriched within that population through positive selection. Signa-
tures of positive selection, though rare in genes, can be useful for the identifica-
tion of those that have played an important role in the adaptation of a species to
its local environment (Bersaglieri et al., 2004; Nielsen et al., 2005). For example,
the frequency of lactose intolerance is low in European populations that have
historically relied heavily on dairy farming for nutrition (Scrimshaw and Murray,
1988). This is due to the rapid expansion of a lactase variant that remains
expressed in adulthood. Carriers of the variant thus have a selective advantage
over those who lose the ability to metabolize lactose. Positive selection at the
lactase gene is characterized by functional variants that lie on high-frequency,
long-range haplotypes with often substantial frequency differences between
populations (Bersaglieri et al., 2004).
Patterns of selection observed in the human genome are not uniform
and in fact vary according to gene function. Balancing selection at immune
system loci can act to sustain a high level of functional diversity relative to other
gene classes (Hughes et al., 2005) and provides a mechanism by which diversity
at antigen recognition sites may be maintained, providing significant host advan-
tage upon immune challenge. In contrast, purifying selection acting at sites of
nonsynonymous nucleotide substitution is manifest as reduced heterozygosity
and involves the process of elimination of variation with only slightly detrimental
effects (Hughes et al., 2003).

C. SNPs in health and disease

It has been estimated that 50,000–200,000 SNPs may be biologically important
(Chanock, 2001; Risch, 2000; Sachidanandam et al., 2001). Nucleotide substitu-
tions in the genome have the potential to directly contribute to disease patho-
genesis, acting in a variety of ways depending on where they occur. Gene-centric
SNPs can have serious consequences for the function or structural stability of a
protein if they cause its primary structure to change. Exonic SNPs that lead to
amino acid substitutions are referred to as “nonsynonymous.” Exonic SNPs are
the best characterized class of genetic polymorphism; they are subject to detec-
tion bias and their functional effects are often readily assayable. The relative
severity of an amino acid substitution may be predicted by consideration of the
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 1. Common Genetic Variation and Human Disease 5

biochemical properties of the side chains in question. Reference tables and

algorithms (e.g., SIFT and PolyPhen) have been developed to aid investigators
in assessing the significance of amino acid substitutions (Grantham, 1974;
Ng and Henikoff, 2003; Ramensky et al., 2002). Many investigators choose
to prioritize the analysis of nonsynonymous SNPs in their genetic association
studies, on the basis that they may be extremely biologically significant.
Nucleotide substitutions in the protein-coding portions of genes some-
times result in the premature insertions of codons that cause the termination of
protein translation. These often become alleles that are effectively null because
their transcribed mRNA is rapidly degraded by nonsense mediated decay (Lykke-
Andersen, 2001). SNPs occurring in the exons of genes that do not alter protein
primary structure are called “synonymous.” Historically, while of interest to
population and evolutionary geneticists, synonymous SNPs had been thought
to be functionally uninteresting. Recent experimental evidence has shown,
however, that they can effect mRNA stability (Capon et al., 2004; Wang et al.,
2005) and alter splicing signals in genes; the latter mechanism is known to be
involved in androgen-insensitivity syndrome, Glanzmann thrombasthenia, and
cerebrotendinous xanthomatosis (Chamary et al., 2006).
SNPs in introns, regulatory, and gene-distant regions can also be func-
tionally important, primarily by affecting gene regulation. A relatively common
variant (MAF of 1–2%), G21210A, in the 3 prime UTR of the prothrombin
gene, F2, increases its expression, and carriers of the minor allele are at signifi-
cantly increased risk for venous thrombosis (Poort et al., 1996). SNPs in the
upstream untranslated region of neuregulin 1 have been associated with schizo-
phrenia and, in particular, with expression levels of splice variants of the gene
(Law et al., 2006). Indeed, SNPs that occur in apparent gene deserts have been
associated with disease risk, three studies having independently identified and
validated variants on chromosome 8 that increase susceptibility to prostate can-
cer and that are located 250 kb away from the nearest gene (Gudmundsson et al.,
2007; Haiman et al., 2007; Yeager et al., 2007).
In some cases, genetic variants may mediate protection from a particular
disease. In the field of infectious diseases especially, there are a number of
examples in which the success of a pathogen is subject to the genetic makeup
of its host. Hope within the HIV research community was triggered by the dis-
covery that a deletion variant of the chemokine receptor gene, CCR5, is highly
associated with increased resistance to HIV infection, even in the face of multiple
exposures to the virus (Liu et al., 1996). Similarly, SNPs in CCR5 and other
chemokine receptor genes have been shown to be associated with disease pro-
gression, substantially waylaying the onset of AIDS (O’Brien and Nelson, 2004;
Smith et al., 1997).
6 Orr and Chanock

D. Other categories of genomic variation

There are many alternative classes of DNA variation that can have an impact on
human health. Short tandem repeats (STRs) and variable number tandem
repeats (VNTRs), collectively termed microsatellites, are head to tail repeats
of multiple copies of a sequence motif, with STRs comprising a smaller number of
individual bases than VNTRs. They are often extremely heterogeneous within a
population and as such are useful for mapping purposes and for establishing
relatedness. Large expansions of trinucleotide repeats can lead to genomic
instability, the classic example being fragile X syndrome. A dinucleotide repeat
(DG8S737) on chromosome 8 has been shown to be strongly associated with
prostate cancer in African-Americans (Cheng et al., 2008; Freedman et al.,
2006), though its functional importance has yet to be established. Whether or
not modest variation in STR and VNTR length impacts on disease remains to be
determined, though evidence suggests that some may act as binding sites for
nuclear proteins (Richards et al., 1993).
Structural variants comprising large regions of variable copy number
occur in the human genome (Iafrate et al., 2004; Sebat et al., 2004) and can have
MAFs>1%. Copy number variants (CNVs) therefore comprise part of the
common genetic variation in a population. It has been estimated that a pair of
individuals from a population will differ by a minimum of 11 CNVs (Sebat et al.,
2004). The technology required to detect and assay CNVs has not reached a
similar level of accessibility and versatility as for that of SNPs; this is reflected
experimentally in a lack of overlap between publications describing CNVs,
largely due to differences in assay methodology (Eichler, 2006). CNVs may
encompass entire genes including promoter regions (Iafrate et al., 2004) and
therefore may have an impact on phenotype. CNVs can have dose effects; the
CCL3L1 gene duplication in HIV highly exposed individuals is a fine example of
how varying gene dosage can alter host susceptibility to infection (Gonzalez et al.,
2005). CCL3L1 copy number is inversely correlated with HIV susceptibility.
We can be certain that complex disease phenotypes will involve genetic con-
tributions from both SNPs and CNVs, but resolving those of the latter will be
slower in the immediate future because of a comparative lack of available
analytical resources.
Insertion and deletion polymorphisms, ranging in size from a few to
several thousand kilobases of DNA, often appear to be in strong linkage disequi-
librium (LD) (see below) with surrounding SNPs (Hinds et al., 2006; McCarroll
et al., 2006). Existing repositories of SNP data may be explored for clues as to
the whereabouts of insertion and deletion polymorphisms because they often
leave telltale traces, including deviation from Hardy-Weinberg equilibrium
(HWE) (McCarroll et al., 2006). Indeed, it may be prudent to reevaluate past
association study data in which SNPs excluded on the basis of deviation from
 1. Common Genetic Variation and Human Disease 7

genotypic proportions expected under HWE because this may indicate underly-
ing structural variation (Wittke-Thompson et al., 2005). Plans are under way to
comprehensively map population-wide structural variation (Eichler et al., 2007).

III. UTILIZATION OF GENETIC VARIATION IN GENE MAPPING STUDIES

The goal of disease gene discovery projects is to identify biologically functional

variants in sets of genes. However, it cannot be overemphasized that the numbers
of such variants are vastly overshadowed by those of functionally silent SNPs and
it is these which are of most relevance to the discussions that follow. SNPs can
serve as surrogate markers for functional variants when mapping disease genes
and this has fueled much of the drive toward characterizing and understanding
genomic variation. A clear distinction must be drawn between SNPs with
biological function and those used solely for the purpose of mapping because
they are utilized differently in genetic association studies (Fig. 1.1). Historically,
much emphasis has been placed on the investigation of candidate SNPs, driven
by a specific hypothesis. But, with the rapid expansion of the characterization of
common variants, the concept of “SNPs as markers” has emerged as the primary
approach, partly because so few SNPs have been adequately characterized in
laboratory evaluations. By analyzing and assaying the distribution of marker
SNPs, we can capture the impact of functional ones in proximity.
Two main approaches have been used to identify disease-causing genes,
namely linkage analysis and association studies. Both methods are similar in that
they use genetic variation to mark genomic loci and then attempt to detect
cosegregation of marker and disease. A sine qua non of any disease mapping
study, whether by linkage or association, is the knowledge of the stable position
and frequency of the markers that are to be used, which can be a daunting
challenge in the context of the rapid evolution of content, knowledge, and tools
for cataloging and display. Initial efforts to discover, validate, and catalogue
SNPs were gene-centric. APOE was one of the first targets of attempts to build
high-density SNP maps for association studies in complex disease (Lai et al.,
1998). Subsequently, large-scale gene resequencing projects have been estab-
lished in an effort to characterize genetic variation within genes of interest for a
number of diseases. The SeattleSNPs discovery resource aims to resequence genes
involved in inflammatory processes (http://pga.gs.washington.edu/), whereas the
Environmental Genome Project focuses upon the genetic components of diseases
with a clear environmental component (Wilson and Olden, 2004). Of particular
interest to cancer molecular epidemiologists is the SNP500Cancer project
(Packer et al., 2006) maintained by the NCI Cancer Genome Anatomy Project
(http://cgap.nci.nih.gov) that aims to resequence genes of significance in cancer
8 Orr and Chanock

i
a b c d e f

ii
Direct test

a b c d e f

iii
Indirect test Indirect test

a b c d e f

iv
1
a c d
2
b f
3
e

Figure 1.1. Direct versus indirect association testing. Part (i) shows six common SNPs as they would
be represented in a population sample. SNP-c is responsible for conferring a disease
phenotype upon carriers. In a direct test (ii), SNP-c would be directly assayed and tested
for association with the disease, perhaps based on prior evidence of structural or
functional consequences of variation at this site. In contrast, the indirect approach
(iii) is agnostic with regard to functional variation. The assayed markers need only be in
LD with the causative variant to achieve a signal of association. The caveat with this
method is that care must be taken to type the appropriate markers needed to ensure
thorough coverage of a given region. In the hypothetical example shown, tests of
association between disease status and genotype at SNP-b, SNP-e, or SNP-f would
prove nonsignificant. Only SNP-a and SNP-d are indirectly associated with the disease.
The reason is shown in part (iv) that illustrates the concept that SNPs arise on
independent haplotypic backgrounds and that many common haplotypes exist at a
given locus (three are illustrated in the example, but in reality many more are likely to
be present). If we assume that SNP-c arose on haplotype 1, we can see that assaying the
SNPs that define haplotypes 2 and 3 will not be useful in demonstrating an association of
this locus with the disease. Instead, to fully analyze this region, we must assay at least one
haplotype “tagging” SNP from each of the observed haplotypes.

in four ethnically diverse populations. A review of a small number of the most

significant SNP databases, along with a brief outline of their relative merits, can
be found in Table 1.1.
Table 1.1. Widely Used SNP Data Repositories

Database Notes No. of SNPs Population Web url References

dbSNP NCBI repository for SNP data from (at pres- >10 million Diverse—no restric- http://www.ncbi. Sherry ST, et al.
ent) 35 organisms. It includes small inser- human SNPS, tion on population nlm.nih.gov/ Nucleic Acids
tion/deletion polymorphisms. No 4.8 million projects/SNP/ Res. 2001; 29:
stipulation as to minimum MAF, therefore validated 308–311
many SNPs are potentially singletons.
HapMap International effort designed to catalogue >5.8 million 4 populations; www.hapmap.org International
common human genetic variation across the 30 Yoruba trios, HapMap
genome in four ethnically distinct popula- 30 Caucasian trios, Consortium
tions. Its primary purpose is to aid in the 45 Chinese indivi- Nature. 2005
identification of haplotype-tagging SNPs duals, and 45 Japa- Oct 27;437
that may be used to facilitate association nese individuals (7063):
study design and as such it is of great value to 1299–1320.
medical geneticists. In addition, it has
yielded much information regarding the
evolutionary genetics of populations.
SNP500 The SNP500 database is home to resequencing >13800 (updated 102 individuals from http:// Packer et al.
data from genes thought to be of importance daily) 4 ethnically di- snp500cancer. Nucleic Acids
in cancer. It aims to provide a framework of verse groups nci.nih.gov/ Res. 2006; 34:
use to molecular epidemiologists in the de- home_1.cfm D617–D621
sign of cancer-based association studies.
Validated sequencing and genotyping assay
conditions are openly available from the
SNP500 website and data may be extracted
preformatted for use in a number of genetic
analysis programs. There is a heavy SNP
selection bias in favor of putative functional
polymorphism and as such, SNP500 is al-
most entirely gene-centric.

(Continues)
Table 1.1. (Continued )

Database Notes No. of SNPs Population Web url References

Gene SNPs/The The premise of the EGP is to identify poly- Approximately 90 sample population http://www. Wilson and
Environmental morphic variation in candidate genes that 30,000 from the polymor- genome.utah. Olden Mol.
Genome are believed to be at the interface between phism discovery edu/genesnps/ Interv. 4:
Project (EGP) genetics and response to environmental resource of the 147–156
stimulus. Approximately 500 genes drawn Coriell Repository
from cell cycle, DNA repair, apoptosis, and including Europe-
signaling, among others, have been chosen an, African-Amer-
for inclusion. It is hoped that the EGP will icans, Mexican,
be valuable in the elucidation of the genetic Native Americans,
components of diseases with strong envi- and Asian-
ronmental etiology. Americans
Seattle SNPs Concentrates on genes with relevance to in- Over 30,700 48 African-Ameri- http://pga.mbt. Na
flammation, but also clotting and heart lung cans and 47 washington.
and blood-related phenotypes. Provides Americans with edu/
assay conditions and resources for assay European ancestry
design.
HGMD This database is particularly useful for physi- More than 50,000 No restriction on http://www. Stenson PD, et al.
cians, researchers, and genetic counselors. It entries, population hgmd.cf.ac.uk Hum Mutat.
aims to collate data on genetic variation approximately 2003 Jun;21
pertaining to human disease. About 70% of 35,000 SNPs (6):577–581.
the lesions described are SNPs, but the re-
mainder comprises the full mutational spec-
trum, from small indels to gross
chromosomal abnormalities. The mutations
are germ line in nature; somatic and mito-
chondrial variants are excluded. Important
to note that the HGMD relies on the opin-
ion of submitters as to the pathogenic sig-
nificance of their entries and as such there
are likely to be many nonfunctional poly-
morphisms in the database.
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