This is the first in a series of 3 articles serving as an introduction to clinicians wishing to read and critically appraise genetic association studies. We summarize the key concepts in genetics that clinicians must understand to review these studies, including the structure of DNA, transcription and translation, patterns of inheritance, Hardy-Weinberg equilibrium, and linkage disequilibrium. We review the types of DNA variation, including single-nucleotide polymorphisms (SNPs), insertions, and deletions, and how these can affect protein function. We introduce the idea of genetic association for both single-candidate gene and genome-wide association studies, in which thousands of genetic variants are tested for association with disease. We use the APOE polymorphism and its association with dementia as a case study to demonstrate the concepts and introduce the terminology used in this field. The second and third articles will focus on issues of validity and applicability.
The building block of DNA is the nucleotide—a sugar (deoxyribose) with a phosphate group at the 5′ carbon and a base (adenine, thymine, guanine, or cytosine) at the 1′ carbon. Nucleotides link together by a bond between the phosphate group of one nucleotide and the 3′ carbon of the previous nucleotide, to form a single DNA strand with a resulting directionality of 5′ to 3′. Two strands with opposite directionality combine to form a double helix that is held together by hydrogen bonds across the bases. Adenine always binds to thymine and guanine always binds to cytosine. The sequence of base pairs encodes the genetic information.
A, Typically, an individual has 23 pairs of chromosomes. One member of each pair is inherited from the mother and one from the father. Chromosomes shown in the karyotype were obtained when the cell was not dividing, stained using Giemsa, and ordered by size. B, The DNA double helix is wound around proteins called histones to form small packages called nucleosomes. The nucleosomes in turn are wound around themselves to form loops that make up the chromosome. The region of the chromosome near the center is called the centromere, and each end is called a telomere. C, The centromere is not exactly at the center of the chromosome, resulting in a shorter arm, named p for petit (French for small) and a longer arm, named q. Chromosome 19 is the site of the APOE gene, which is composed of sequences with regulatory functions (untranslated regions) and sequences with coding functions. Regions of the gene that are spliced out during transcription to messenger RNA are called introns. The remaining regions, exons, contain the sequences that code for the final protein product.
During transcription, the DNA double helix is split apart, and RNA polymerase synthesizes messenger RNA (mRNA) using one DNA strand as a template. Sections of the primary mRNA transcript, called introns, are spliced out to form the mature mRNA, which moves into the cytoplasm. The ribosome uses the mRNA sequence to build the protein. A specific sequence of 3 bases codes for each amino acid, which is delivered to the ribosome by transfer RNA. UTR indicates untranslated region.
DNA polymorphisms include deletions, in which a DNA sequence is missing compared with the common allele, and insertions, in which a DNA sequence is added compared with the common allele. Repeats may also occur, in which the same sequence repeats multiple times. Depending on the size of the repeating unit and the number of repeats, these variants may have different names, such as satellites, microsatellites, minisatellites, or copy number variants. Single-nucleotide polymorphisms (SNPs), variations at a single base-pair location, are the most common type of polymorphism in the human genome.
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